Perivascular adipose tissue in age-related vascular disease

Ageing Research Reviews 59 (2020) 101040

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Review

Perivascular adipose tissue in age-related vascular disease

T

Marcelo Queiroz, Cristina M. Sena* Institute of Physiology, iCBR, Faculty of Medicine, University of Coimbra, Portugal

A R T I C LE I N FO

A B S T R A C T

Keywords: Age-related vascular disease Aging Aorta aneurysm Arterial stiffness Atherosclerosis Inflammation Metabolic disorders Perivascular adipose tissue Type 2 diabetes

Perivascular adipose tissue (PVAT), a crucial regulator of vascular homeostasis, is actively involved in vascular dysfunction during aging. PVAT releases various adipocytokines, chemokines and growth factors. In an endocrine and paracrine manner PVAT-derived factors regulate vascular signalling and inflammation modulating functions of adjacent layers of the vasculature. Pathophysiological conditions such as obesity, type 2 diabetes, vascular injury and aging can cause PVAT dysfunction, leading to vascular endothelial and smooth muscle cell dysfunctions. We and others have suggested that PVAT is involved in the inflammatory response of the vascular wall in diet induced obesity animal models leading to vascular dysfunction due to disappearance of the physiological anticontractile effect. Previous studies confirm a crucial role for pinpointed PVAT inflammation in promoting vascular oxidative stress and inflammation in aging, enhancing the risk for development of cardiovascular disease. In this review, we discuss several studies and mechanisms linking PVAT to age-related vascular diseases. An overview of the suggested roles played by PVAT in different disorders associated with the vasculature such as endothelial dysfunction, neointimal formation, aneurysm, vascular contractility and stiffness will be performed. PVAT may be considered a potential target for therapeutic intervention in age-related vascular disease.

1. Introduction Vascular tone is regulated by local, hormonal and neural mechanisms interconnected. The local control is a crucial mechanism in the regulation of blood pressure and nutrient delivery to peripheral tissues and all vascular cell layers are actively involved. Perivascular adipose tissue (PVAT) is the adipose tissue depot that surrounds different vascular beds (except for capillaries, pulmonary and cerebral blood vessels). Three decades after the first publication (Soltis and Cassis, 1991), PVAT is finally having protagonist in the field of vascular biology. More than just an anatomic support for the vessel it is now widely accept that PVAT, due to its paracrine/endocrine features, has a huge impact on vascular homeostasis and function exerting both protective and deleterious effects on the vasculature depending on the pathophysiological milieu (Fernández‐Alfonso et al., 2018; Nosalski and Guzik, 2017; Kim et al., 2019a). Healthy PVAT exerts anticontractile effects with protective beneficial effects due to the release of relaxing factors such as adiponectin (Fésüs et al., 2007), angiotensin 1–7 (Lee et al., 2009), H2S (Wójcicka et al., 2011), nitric oxide (NO; Gao, 2007) and palmitic acid methyl esters (Lee et al., 2011). In addition, PVAT-derived adipocytokines include adiponectin, leptin, visfatin,

omentin, chemerin and resistin capable of regulating vascular function (Mattu and Randeva, 2013). PVAT exhibits regional differences and heterogeneity along the vascular tree due to the presence of adipocytes white, brown or both (Brown et al., 2014). White adipocytes are anabolic, unilocular, with a single lipid droplet occupying most of the cytoplasm, low mitochondrial content and metabolic rate while brown adipocytes contain many lipid droplets with multilocular appearance, utilize glucose and lipids to generate heat (catabolic) contributing to the regulation of body temperature and are associated with improved cardiometabolic health (Chang et al., 2012). Recent studies have described that white adipocytes may differentiate into beige adipocytes in response to certain stimulus such as cold exposure. Beige adipocytes resemble brown adipocytes with high levels of uncoupled protein-1 involved in thermogenesis (Hildebrand et al., 2018). In rodents, thoracic aorta is surrounded by brown-like adipocytes essential in maintaining vascular homeostasis and in the regulation of intravascular temperature (Xiong et al., 2017; Chang et al., 2018), whereas the abdominal aorta contains mainly white adipocytes and some brown adipocytes in PVAT (both in rodents and humans). The phenotype of human thoracic aorta is unclear, some authors reported brown adipocytes while others described

⁎ Corresponding author at: Institute of Physiology, Faculty of Medicine, University of Coimbra, Subunit 1, polo 3, Azinhaga de Santa Comba, Celas, 3000-354, Coimbra, Portugal. E-mail address: [email protected] (C.M. Sena).

https://doi.org/10.1016/j.arr.2020.101040 Received 7 November 2019; Received in revised form 31 January 2020; Accepted 23 February 2020 Available online 26 February 2020 1568-1637/ © 2020 Elsevier B.V. All rights reserved.

Ageing Research Reviews 59 (2020) 101040

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Fig. 1. Crosstalk between the perivascular adipose tissue (PVAT) and blood vessels. Emphasis for the bidirectional communication between PVAT and vascular wall components “outside to inside’’ (A, B; upper arrows) and “inside to outside’’ (C,D; lower arrows) theory of interactions in development of vascular pathologies. A- Mediators liberated by PVAT associated with vasorelaxation and vascular health; B- Mediators liberated by PVAT associated with vascular diseases and vasoconstriction; C- Factors in circulation and released locally able to influence PVAT phenotype under physiologic conditions (antioxidants and anti-inflammatory agents). D- Factors in circulation and released locally able to influence PVAT phenotype under pathologic conditions [oxidative stress (lipid peroxidation) and proinflammatory agents]. A, adrenaline; ADRF, adipocyte derived relaxing factor; Ang 1–7, angiotensin 1–7; Ang II, angiotensin II; CCL2, C-C motif chemokine ligand 2; CxCL3, C-X-C motif chemokine3; CxCL10, C-X-C motif chemokine10; H2S, hydrogen sulphide; ICAM1, intercellular adhesion molecule 1; IFN-γ, interferon γ; IL, interleukin (IL); NA, noradrenaline; NO, Nitric oxide; PAI-1, plasminogen activator inhibitor1; PAME, palmitic acid methyl esters; PGE2, prostaglandin E2; PVAT, perivascular adipose tissue; RANTES, regulated on activation normal T cell expressed and secreted; TNF-α, tumour necrosis factor- α; TxA2, thromboxane A2; VCAM1, vascular cellular adhesion molecule 1.

subcutaneous WAT or interscapular BAT development) due to the deletion of the master regulator of adipogenesis, the peroxisome proliferator–activated receptor-γ (PPAR γ), in VSMCs. These data suggest that PVAT shares a developmental origin with VSMCs. PVAT adipocytes may be derived from VSMCs progenitors, neural crest cells and other unidentified lineages (Chang et al., 2012; Fu et al., 2019). Indeed, recent studies suggest that thoracic-PVAT is a heterogeneous adipose tissue derived from multiple progenitor cells, and different anatomical locations of thoracic-PVAT may have different origins and distinct physiological functions (Ye et al., 2019). The phenotypical differences and heterogeneity of PVAT surrounding different vessels, suggests distinct PVAT development origins with local specificity.

the presence of white adipocytes in PVAT (Gao et al., 2005; Fitzgibbons et al., 2011). Adipocytes are the major cell type of PVAT. PVAT also contains a stromal fraction (Silva et al., 2017; Gronthos et al., 2001) with pre-adipocytes, stem cells (Zuk et al., 2002), fibroblasts, inflammatory cells [(macrophages (Antonopoulos et al., 2014), lymphocytes (Srikakulapu et al., 2017) and eosinophils (Withers et al., 2014)], nerves and vascular cells that form the adipose tissue microvasculature (Silva et al., 2017). PVAT is closely adjacent to the vascular wall enabling a paracrine exchange of many factors through outside-to-inside signalling between PVAT and vascular cells (Fig. 1). In this manner, PVAT modulates vascular smooth muscle cells (VSMCs) tonus, cell proliferation and migration (Szasz and Webb, 2012). Endothelial cell function is also modified by PVAT secretome albeit the mechanisms (involving vasa vasorum) are not completely clarified. Pro-inflammatory and oxidative stimuli can alter PVAT phenotype, suggesting a bidirectional crosstalk between the PVAT and the vascular system (Fig. 1). PVAT becomes dysfunctional (ie. loses its vasoprotective effects) and modifies the secretome producing contractile and pro-inflammatory cytokines and chemokines related with several known vascular disorders (Fig. 2). Traditionally, to evaluate arterial function, ex vivo, arteries are mounted without PVAT. However, it is not the best physiological approach since blood vessels, in our body, are surrounded by this layer of tissue with a major impact on their functional behaviour (Agabiti-Rosei et al., 2018).

1.2. PVAT innervation Previous studies have provided evidence of sympathetic innervation in PVAT (Bulloch and Daly, 2014; Darios et al., 2016). Ayala-Lopez and co-workers have studied the interaction between sympathetic innervation, PVAT and smooth muscle relaxation showing that PVAT adipocytes can transport and store noradrenaline (Ayala-Lopez et al., 2015). More recently, sympathetic stimulation within mesenteric PVAT triggers the release of adiponectin via β3-adrenoceptor activation leading to PVAT-dependent vasodilation. PVAT acts as a reservoir of catecholamines, released by sympathetic nerve ending, avoiding smooth muscle contraction (Saxton et al., 2018). These studies point to an interaction between PVAT adipocytes and sympathetic innervation to balance pro-contractile and anticontractile effects of PVAT. In addition, increased sympathetic nerve activity/influence on the vasculature occurs during aging, due to the release of endogenous adrenoceptor agonists. Noradrenaline storage in PVAT adipocytes may be dysregulated in aging or age-related diseases. Sensory nerves within PVAT promote neurogenic vasorelaxation and crosstalk with adipocytes, leading to leptin-induced relaxation mediated by calcitonin gene-related peptide, a mechanism that is reduced in obesity-induced adipose tissue dysfunction due to hypoxia (Abu Bakar et al., 2017). Indeed, innervation of PVAT may be the crucial link between increased adiposity and vascular disease and its

1.1. PVAT origin PVAT may be considered as the fourth type of adipose tissue with an origin developmentally different from other adipose tissues [brown adipose tissue (BAT), white adipose tissue (WAT) and beige adipose tissue]. The origin of PVAT adipocytes remains to be fully elucidated and depends on the location along the vascular tree. Thoracic PVAT cells originate from Myf5–precursors different from classical brown adipocytes (Sanchez-Gurmaches and Guertin, 2014). Importantly, Chang et al. (2012) have generated mice completely devoid of PVAT in the aortic and mesenteric regions (with intact gonadal/inguinal/ 2

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Fig. 2. Scheme outlining the major consequences of dysfunctional perivascular adipose tissue (PVAT) on the vascular wall. The dysfunction in PVAT due to several causes (including metabolic dysfunction, hypertension, aging and others) leads to changes in the adipokine profile and an increased secretion of pro-inflammatory cytokines, both associated with inflammation and hypoxia. Consequently, there is a loss of the PVAT anticontractile phenotype. All these changes might contribute to enhance cardiovascular risk factors like insulin resistance, vascular calcification, neointima formation, and arterial stiffness.

of chemokines and pro-inflammatory adipokines, contributing to endothelial dysfunction (Sena et al., 2017). Moreover, other studies also suggested that obesity promotes “whitening of BAT” in thoracic periortic adipose tissue (Police et al., 2009). More recently, alterations of PVAT either in its function or morphology have been observed in aging studies and in a wide variety of vascular pathologies like atherosclerosis, hypertension, abdominal aortic aneurysm and cardiometabolic disorders such as diabetes (Nosalski and Guzik, 2017; Piacentini et al., 2019; Zou et al., 2016; Azul et al., 2019). Are these modifications a cause or a consequence in those pathological conditions? Moreover, PVAT´s clinical relevance remains elusive and more study in humans are necessary to clarify this matter. Nevertheless recently, researchers have proposed PVAT imaging as an important tool in cardiovascular disease with great potential to be integrated in clinical risk stratification (see Section 3, below).

role should be elucidated in aging and age-related diseases as it may represent a novel target in the treatment of cardiovascular diseases. 2. PVAT impact on vascular pathology Under pathological conditions, PVAT has a dual role. In an initial phase it is protective and exerts anticontractile activity but with the persistency of the risk factors and the progression of a pathology it modifies its phenotype and adversely impacts the vascular wall. The deleterious vascular effects described so far include: 1) loss or reduction of anticontractile PVAT effects; 2) promotion of atherogenesis, vascular hypertension, inflammation, oxidative stress, remodelling and calcification; 3) contribution to vascular insulin resistance, inflammation and hypoxia; 4) contribution to the development of atherosclerotic plaques; 5) contribution to age-related arterial stiffness; 6) augmentation of cardiovascular risk in menopause (Gollasch, 2017; Fernández‐Alfonso et al., 2018). There is a clear connection between PVAT dysfunction, increased pro-inflammatory and pro-contractile factors and increased risk of hypertension (recently reviewed by Nosalski and Guzik, 2017; Fernández‐Alfonso et al., 2018). PVAT modifications in obesity have also been extensively evaluated (Xia and Li, 2017). In obesity, PVAT volume and adipocyte size increase significantly with altered PVAT phenotype (pro-inflammatory and pro-oxidant) and secretome (recently reviewed by Saxton et al., 2019). We have previously shown that PVAT from aged Wistar rats fed with high-fat diet have increased expression

2.1. Vascular aging Aging is an independent, nonmodifiable risk factor for vascular disease and involves functional, structural, and mechanical changes in arteries (Lakatta and Levy, 2003; Meyer et al., 2016). Vascular aging hallmarks include endothelial dysfunction, reduced vascular elasticity, and increased stiffness. In addition, vascular aging may be accelerated due to several risk factors such as increased blood pressure, impaired glucose and lipid homeostasis, lifestyle factors (smoking, alcohol, salt intake) and disease conditions. 3

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decade researchers started to study its importance.

Aging promotes superoxide production in the PVAT and contributes to arterial stiffness (Fleenor et al., 2014; Donato et al., 2018). In addition, it was previously described that aging worsens neointima lesions after balloon angioplasty through promoting macrophage infiltration and higher sensitivity of VSMCs to proliferation stimuli (Eghbalieh et al., 2012; Rodriguez-Menocal et al., 2014). Moreover, Agabiti-Rosei et al. (2017) found that the anticontractile effect of PVAT was reduced in mesenteric arteries from a senescence-accelerated prone mouse model. In addition, a recent study highlighted that loss of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) in aged resident stromal cells in the PVAT contributes to vascular remodelling via decreased brown adipogenic differentiation capacity (Pan et al., 2019). Indeed, BAT activity is decreased in aging (Van Marken Lichtenbelt et al., 2009). In fact, periaortic adipose tissue (BAT like) in both animal models of obesity and in aged human subjects also presents reduced activity (Police et al., 2009). PVAT modifications during aging may involve a brown‐to‐white transition in adipocyte phenotype and may be a driving factor of vascular disease (Kong et al., 2018; Pan et al., 2019). Re-establishing the brown phenotype of PVAT could be a potential new target for ameliorating vascular dysfunction in age‐related vascular disease (Aldiss et al., 2017; Kiefer et al., 2012; Mattson, 2010). Aging also affects the morphology of periaortic adipose tissue. Aortic PVAT from aged mice contains a mixture of both multilocular brown adipocytes and unilocular white adipocytes (Padilla et al., 2013). PVAT “whitening” promotes higher levels of inflammatory and pro-oxidant factors. Similarly, thoracic PVAT of aged rats exhibits an increment in lipid deposition and CD11c expression (marker of proinflammatory macrophages) highlighting a potential role for an inflammatory PVAT in the vascular dysfunction in aging (Padilla et al., 2013). In addition, Bailey-Downs et al. (2012) described that aging exacerbates obesity induced oxidative stress and inflammation in PVAT. PVAT from obese aged mice (24-month-old) exhibited increased oxidative stress due to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase upregulation, reduced endothelial nitric oxide synthase (eNOS) expression and an increment in inflammation (BaileyDowns et al., 2012). Utilizing PVAT conditioned media obtained from the PVAT of obese aged mice they found that the pro-inflammatory cytokines and chemokines secreted by PVAT elicited oxidative stress and vascular dysfunction, highlighting the PVAT secretome role in aging and obesity. Moreover, recent studies have shown that mineralocorticoid receptor activation leads to mitochondrial dysfunction and premature aging in the adipose tissue of obese db/db mice and lost the beneficial anticontractile properties of PVAT (Lefranc et al., 2019). Epigenetic changes, known to be incremented in aging, occur in different locations of the vasculature wall: 1) endothelium, 2) PVAT adipocytes, and 3) inflammatory cells; all promote modifications eliciting oxidative stress, inflammation and lead to endothelial and vascular dysfunction. A very limited amount of information is known regarding epigenetic control of PVAT. It was previously suggested that epigenetic repression of PGC-1α in PVAT could explain the impaired uncoupling protein-1 (UCP-1) and PPAR-γ expression in epicardial fat of rats fed with high-fat-diet (Shore et al., 2010). Epigenetic repression of genes such as adiponectin, leptin receptor, PR domain containing 16 (PRDM16), PGC-1α, UCP-1 has been previously suggested in a hypothetical model of dysfunctional PVAT in metabolic syndrome (Blirando, 2016). In addition, epigenetic pathways are crucial regulators of eNOS and adipokine (adiponectin, leptin) genes possibly modifying the anticontractile activity of PVAT. Inflammation may induce a whitening of the PVAT by epigenetic repression of its thermogenic programme (Blirando, 2016). More studies are necessary to clarify this hypothesis. Age-related vascular tissue dysfunction includes inflammation, macromolecular damage, progenitor cell dysfunction, cellular senescence, among others. The role of PVAT in age-related vascular diseases is crucial and deserves further investigation. Indeed, only in the last

2.2. Arterial stiffness A pulse wave is generated during each cardiac contraction and transmitted through conduit vessels until it finds peripheral resistance or points of arterial branching where it is partially reflected due to impedance mismatch (Chirinos et al., 2019). The shape and velocity of the reflected wave depend on peripheral vascular resistance, elasticity of arteries, and central blood pressure (Lyle and Raaz, 2017; Chirinos et al., 2019). Arterial aging negatively affects pulsatile hemodynamic. In young subjects, arteries are more elastic. Thus, the reflected wave is slow and reaches the heart during diastole, augmenting the diastolic pressure, improving coronary perfusion (Nichols et al., 2011) and not affecting cardiac afterload. In aged individuals, pulse wave velocity (PWV) increases, resulting in a reflected wave that returns to the heart during systole rather than in diastole. This augments systolic blood pressure, leading to an increase in cardiac afterload and a reduction in coronary perfusion (Nichols et al., 2011; Safar et al., 2003; Chirinos et al., 2019). Several large landmark studies reported an age-related progression of arterial stiffness (Mitchell et al., 2004; AlGhatrif et al., 2013; Vaitkevicius et al., 1993). Indeed, arterial stiffness is a consequence of the aging process and an early step in the development of vascular disease (Aroor et al., 2017). Vascular aging can be assessed by use of arterial stiffness analysis. Several invasive and non-invasive methods have been previously described. Non-invasive measurements of arterial stiffness by PWV are the most frequently used and validated techniques (van Sloten et al., 2014) as prospective markers for cardiovascular risk stratification (Laurent et al., 2006; Mancia et al., 2013). Senescent vascular changes include several structural and functional modifications. Structurally, arterial diameters increase, subintimal thickening progresses, VSMCs hypertrophy (increased intima/media thickness), collagen accumulate, and elastin degeneration and fragmentation happen, fibrosis and calcification occur (increased arterial fibrosis and stiffness). Functionally, senescent endothelial cells became dysfunctional with reduced NO bioavailability and impaired vasodilation leading to atherogenesis and increased susceptibility to vascular dysfunction (Fig. 3). Adventitia, the outermost vascular layer, regulates vascular tone, nutrition supply and participates in local immune responses in both aging and atherosclerosis (Stenmark et al., 2013; Xu et al., 2017). Aging promote T lymphocyte infiltration and inflammation in this vascular layer (Gräbner et al., 2009). Overall, as arteries age, inflammation and oxidative stress increase in adventitial layer, modifying the vascular wall, contributing to vasoconstriction and remodelling and leading to vascular dysfunction. Impaired vasa vasorum function and innervation occurs in aging as well as PVAT dysfunction (Rademakers et al., 2013; Chang et al., 2018). Moreover, the role of PVAT in vessel compliance and arterial stiffness is largely unknown. Is healthy PVAT beneficial for vessel compliance and dysfunctional PVAT promotes arterial stiffness? Previous studies suggested that PVAT may be involved in arterial stiffness. Some authors defend a potential “outside-to-inside” mechanism that leads to arterial stiffness mediated by complement C3 and C4 in PVAT binding to collagen and elastin fibers in the adventitia (Shields et al., 2011). In addition, the aortic PVAT of ob/ob mice was pro-inflammatory and pro-oxidative and associated with increased aortic PWV (Chen et al., 2013). Moreover, it was previously observed that aortic perivascular adipose-derived interleukin-6 fosters arterial stiffness in low-density lipoprotein receptor deficient mice (Du et al., 2015). More recently it was shown that the aortic PWV was greatly increased in mice lacking PVAT. In contrast, high-fat diet feeding in animal models induced PVAT hypertrophic expansion, associated with mitoNEET inhibition, increased PVAT inflammation, and fibrosis, leading to arterial stiffness (Chang et al., 2018). MitoNEET is a dimeric 4

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Fig. 3. Various mechanisms occur during vascular aging in PVAT. Aging promotes an increment in oxidative stress and inflammation in PVAT that lead to major alterations including structural and functional changes, extracellular matrix remodelling, endothelial and VSMCs dysfunction. Overall this leads to decrease flexibility and increase stiffness in aged arteries. CCL2, C-C motif chemokine ligand 2; CRP, C reactive protein; IL-6, interleukin-6; M, macrophage; PGC-1α, peroxisome proliferatoractivated receptor γ coactivator-1α; PVAT, perivascular adipose tissue; TNF-α, tumour necrosis factor-α; TGF-β, Transforming growth factor-β; VSMCs, vascular smooth muscle cells.

The dysfunction of PVAT plays a major role in AAA development. Piacentini et al. have shown that gene expression in PVAT is related with AAA in a locally limited manner. They have observed different gene expression in dilated and normal portions of aneurysms. Dysfunctional PVAT exhibited an enhanced expression of inflammatory response genes with a specific subset that allows to discriminate between PVAT and other adipose tissues depots. The identification of this genes proves that PVAT inflammation is in the origin of AAA and confirms that the alterations in PVAT are associated with the AAA pathogenesis (Piacentini et al., 2019). These findings also confirm that PVAT recruits immune cells, such as T cells and macrophages into the adventitia layer, and inflammation in the vascular wall contributes to the development of aneurysm. Aging, obesity and environmental risk factors augment the entry of leukocytes into the vasculature, which leads to the accumulation of macrophages in areas of the aorta that are more prone to develop aneurysms (Fernández‐Alfonso et al., 2018; Villacorta and Chang, 2015). The recruitment of macrophages and their precursors plays a major role in AAA development. Patients with AAA exhibited an increment of the CD14 macrophage expression in aorta, corroborated with other findings in mice with CD14-deficient that are resistant to AAA formation. IL-6 can potentiate the up-regulation of CD14 expression and CD14-dependent chemotaxis of human THP-1 monocytes treated with PVAT conditioned media suggesting that PVAT-derived pro-inflammatory factors might promote active macrophage infiltration and induce aneurysmal development (Villacorta and Chang, 2015). In cardiovascular diseases, angiotensin-II (Ang. II) has a central role modulating VSMCs proliferation, inflammation and oxidative stress. Ang. II is often used to induce aortic aneurysms in mouse experimental models (Police et al., 2009). Using this model, Sakaue and associates found that genetic deletion of Ang-II type 1 receptor (AT1a) from visceral PVAT leads to an attenuation of aneurysm development: The mechanism involves the inhibition of macrophage recruitment mediated by osteopontin, a protein involved in inflammation, tissue repair and remodelling (Sakaue et al., 2017). The deletion of AT1a receptor inhibits matrix metalloproteinases (MMP-2 and MMP-9) activity as well as macrophage infiltration in both, adipose tissue and aorta, preventing the effects of Ang-II and high fat diet adipocyte hypertrophy, macrophage switching (M2 to M1) and accumulation (Krueger et al., 2017; Police et al., 2009).

mitochondrial outer membrane protein important in the regulation of lipid homeostasis and mitochondrial function. MitoNEET in PVAT prevents arterial stiffness in aging mice (Chang et al., 2018). More studies are clearly necessary to clarify the role of PVAT in vascular stiffness in humans. 2.3. Aorta aneurysm Aneurysms are the most prevalent abdominal and lower extremity disease after atherosclerosis. The abdominal portion of the aorta is the most frequent location for this pathology (Sagan et al., 2012). Moreover, it was previously described that loss of brown-like PVAT properties, around thoracic aorta, promoted the development of aneurysm formation (Hamblin et al., 2010) in mice. Abdominal aortic aneurysms (AAA) are characterized as a permanent and progressive dilatation of the diameter of the aorta of at least 1.5 times the normal size the blood vessel (> 3 cm). This pathology presents a high risk because even though aneurysms are frequently asymptomatic, they can untimely continue to grow and a fatal rupture may occur (Aggarwal et al., 2011; Fernández‐Alfonso et al., 2018; Kurobe et al., 2013; Piacentini et al., 2019; Shimizu et al., 2006). The aneurysm is a disorder of the connective tissue with loss of structural integrity and weakening of the vessel wall, as a consequence of the degradation and destruction of extracellular proteins of the vessel wall due to chronic inflammation, activation of metalloproteinase, vascular smooth muscle depletion, phenotype switching and oxidative stress (Kugo et al., 2019; Piacentini et al., 2019; Villacorta and Chang, 2015). Morphologically AAA tend to be fusiform and with symmetrical circumferential enlargement involving all layers of the aortic wall. Less common forms of aneurysms show a saccular form, with aneurysmal degeneration only in the circumference part of the aorta (Shimizu et al., 2006). The incidence of AAA increases especially with age, sex, ethnicity and smoking habits, but other risk factors like obesity, high cholesterol, diet and hereditary factors can also instigate the formation of aortic aneurysms (Aggarwal et al., 2011; Piacentini et al., 2019). Men are more prone to develop aortic aneurysms than women and usually this pathology occurs 10 years early in men than in women. Age wise, the risk of AAA increases after 60 years of age (Aggarwal et al., 2011; Shimizu et al., 2006). 5

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AAA development in humans.

In leptin deficient obese mice, Zhang and co-workers demonstrated that Ang-II infusion increases the incidence of aortic aneurisms (AA). The authors presented evidence that high fat diet instigates adventitial inflammation. This study linked PVAT dysfunction and AA formation in Ang-II infused obese mice. In addition, platelet derived growth factor-D (PDGF-D) was expressed in PVAT of obese mice and promotes expression and proliferation of inflammatory factors in adventitial fibroblasts. Its inhibition significantly reduces the development of aortic aneurysms (Zhang et al., 2018). Aneurysm formation often coexist with atherosclerosis together with an active involvement of various inflammatory cells. These immune cells are observed in PVAT and luminal thrombi and are, in part, linked with advanced atherosclerotic plaques, and increase the susceptibility of AAA formation. Leukocytes produce proteases like cathepsins capable of destroying cells within the vasculature (Folkesson et al., 2016). In early atherogenesis the expansion of the intima is a result of both, lipid accumulation and recruitment of inflammatory cells. When the inflammatory conditions persist Th1 cytokines like interferon γ (IFNγ) produced by activated leukocytes act on endothelial cells, macrophages and VSMCs. Then the infiltrated cells and the activated aortic wall cells secrete inflammatory mediators like chemokines, adhesion molecules and costimulatory molecules, and PDGF. Those mediators lead to further recruitment of VSMCs and inflammatory cells and can also promote collagen production. These mediators increase migration, proliferation and lead the VSMCs to synthetize extracellular matrix that cause expansion of the intima and lumen obstruction. Reactive oxygen species, autoimmune factors, smoking or even genetic predisposition can induce expression of Th2 cytokines from B and T cell, mast cells, macrophages, natural killer cells and block IFNy signaling causing macrophages and VSMCs to produce leukotrienes and elastolytic MMP-9 and MMP-12, serine proteinases or cathepsins. These proteinases will deteriorate the elastic lamellae leading to aneurysm development (Shimizu et al., 2006). Adipocytes uncharacteristically appear in aortic aneurysms in both humans and hypoperfusion induced AAA models. In the latter, ruptured aortic aneurysms show a considerable higher number of adipocytes in the adventitial wall in comparison with non-ruptured AAA walls. Collagen fibers around adipocytes significantly decrease in comparison with areas without adipocytes, contrasting with the inflammatory cells and MMPs with an opposite distribution (higher in areas surrounding adipocytes compared with areas without them; Kugo et al., 2018, 2019). Vasa vasorum stenosis promotes the degradation of vascular fibers linked with hypertrophic dysfunctional adipocytes. This leads to local chronic inflammation through increased secretion of adipocytokines like C-C motif chemokine ligand 2 (CCL2), tumour necrosis factorα (TNF-α), interleukin (IL)-6, and MMP-2 and MMP-9 that promote vascular wall weakness (Kugo et al., 2018; Tanaka et al., 2015). Metalloproteinases degrade the collagen fibers surrounding the adipocytes, forming vulnerable areas more susceptible to rupture. The increment in mass and number of adipocytes in the vascular wall reflects a higher rupture risk of AAA (Doderer et al., 2018; Hashimoto et al., 2018; Kugo et al., 2018). Human aneurysm studies usually evaluate later phases of the disease and do not emulate the initial conditions that lead to the early stages of aortic dilatation. In vivo studies in animal models can help to understand the function of the innate and adaptative immunity in the beginning of the aneurysm formation. Unfortunately, there is no consensus in the scientific community regarding the best animal model to study aneurysm formation. Elastase perfusion and Ang-II infusion or local treatment with CaCl2 result in aneurysm formation in animal models, those treatments use very high doses that we cannot found physiologically, to induce the aortic expansion. Therefore, those models are not the best solution to replicate the inflammatory process that triggers aneurysm formation, in humans (Police et al., 2009; Shimizu et al., 2006). Further studies are necessary to clarify the role of PVAT in

2.4. Atherosclerosis Atherosclerosis is one of the main causes of cardiovascular diseases with high morbidity and mortality rates worldwide. Therefore, it is crucial to understand the mechanisms associated with its aetiology and progression in order to find new and more efficient therapeutic approaches (Antoniades et al., 2019a, b; Pan and Reilly, 2019). The identification of novel pathways and targets for treatment will enable better outcomes in the future management of patients at risk. Atherosclerosis is a multifactorial and complex chronic disease that affects several vascular beds (Haberka et al., 2019; Henrichot et al., 2005). It can be defined as a thickening and hardening of the arterial walls caused by accumulation and retention of LDL (low density lipoprotein) particles and immune cells (macrophages and T-cells) in the tunica intima, proliferation and migration of VSMCs and endothelial dysfunction. The atherosclerotic plaques are observed in mid-to-large size arteries, between the luminal endothelial cell layer and the medial layer of contractile VSMCs. Plaques usually appear early in life and expand slowly over the years thought uptake of circulating lipoproteins, recruitment of inflammatory cells from blood, migration of VSMCs. This pathology when untreated can progress asymptomatic and may lead to dead due to an atherothrombotic event such as thrombosis, myocardial infarction and stroke (Henrichot et al., 2005; Hildebrand et al., 2018; Pan and Reilly, 2019). The impact of atherosclerosis depends on the location, even though it is a systemic disease that shares common risk factors. The main risk factors for the development and progression of atherosclerosis are aging, hypertension, smoking and diabetes (Haberka et al., 2019). Inflammation is one of the hallmarks in atherosclerosis aetiology and progression and a key element in the formation of the atherosclerotic plaques (Kim et al., 2019b). An early step in atherosclerosis is the presence of endothelial dysfunction which in turn is responsible for the increasing accumulation of LDL due to the increased vascular permeability. The retained LDL modify and suffer processes of oxidation and glycation beginning the low-grade inflammation (Tabas et al., 2015). The innate inflammatory response activates endothelial cells resulting in the infiltration of monocytes that will then differentiate into macrophages. This process occur in the sub-intimal space and the accumulation of LDL in the macrophages ultimately transforms them into the foam cells, typical of atherosclerosis. B-cells and T-cells also have an important role in the progression of the atherosclerotic process, since they infiltrate the intima after the endothelial cell activation (Hildebrand et al., 2018; Libby et al., 2009). Inflammation markers have been associated with cardiovascular risk prediction, independently of previous established cardiovascular risk factors. Biomarkers like high sensitivity C-reactive protein (hsCRP) and IL-6 are used in the detection of systemic inflammation. Importantly, recent studies highlighted the importance to monitor specifically the local modifications promoted by inflammatory processes in the arterial wall and adjacent PVAT, in order to find new and more precise biomarkers for vascular disease (Antoniades et al., 2019a, 2019b; Margaritis et al., 2013). PVAT, as previously discussed, is a source of various vasoactive molecules with potential impact in the underling mechanisms of atherosclerosis formation and progression (Kim et al., 2019b). Several studies both in humans and animal models have linked PVAT with atherosclerosis. One of the theories for the involvement of PVAT in atherogenesis is the “outside to inside” signalling. This hypothesis suggests that external factors incite the release of pro-inflammatory mediators by PVAT that will in turn instigate the infiltration of macrophages and immune cells into the vessel wall, leading to endothelial dysfunction, monocyte adhesion, hypercoagulability and plaque formation (Szasz and Webb, 2012; Szasz et al., 2013). The inflammation associated with PVAT has been responsible for 6

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cold temperatures reduce atherosclerosis occurrence due to the browning of adipose tissue depots (see Section 4.7, below; van Marken Lichtenbelt et al., 2009; Pan et al., 2018). The thermogenic properties of PVAT reduce plasma triglyceride levels leading to a consequent reduction in atherosclerosis (Brown et al., 2014). Indeed, the loss of PVAT in an artery causes temperature loss and endothelial dysfunction and promotes atherosclerosis in mice (Chang et al., 2012). In addition, Baltieri et al. (2018) recently described that upregulation of eNOS in thoracic PVAT of hypercholesterolemic LDL receptor knockout mice protects against endothelial dysfunction highlighting the role of PVAT derived NO as an anti-atherogenic molecule (Baltieri et al., 2018). PVAT-derived adiponectin also has a protective role in carotid arteries of ApoE knockout mice (Li et al., 2015) inhibiting plaque formation while adiponectin exogenous administration protects aorta from atherosclerotic injury (Wang et al., 2014). These studies confirm that PVAT serves has an initial protector of the vascular wall against oxidation or inflammatory stimuli that trigger the beginning and the progression of atherosclerosis. Aging is an important risk factor for the development of atherosclerosis. The mechanisms are pleotropic and involve oxidation (Higashi et al., 2012). It is well established that oxidative stress is enhanced in aging functioning as an accelerator of the atherosclerotic process. LDL modifications are due to oxidation processes leading to the beginning of the atherosclerotic process. The infiltration of immune cells establishes a pro-inflammatory status that leads to oxidative stress creating a vicious cycle. The pro-oxidant stimulus induce apoptotic cell death and premature cell senescence in various tissues and cell types, and therefore both processes are intimately intertwined (Navab et al., 2004; Witztum and Steinberg, 2001; Higashi et al., 2012). Endothelial dysfunction and oxidative stress are the basis of the atherosclerotic process (Finkel and Holbrook, 2000; Higashi et al., 2012; Navab et al., 2004) and are exacerbated in aging. The phenotype of PVAT is altered in aged animal models and can be ameliorated with exogenous administration of adiponectin (Sena et al., 2017). It is crucial to understand and increase the knowledge in this area to develop novel therapeutic approaches.

myofibroblast recruitment and proliferation that contributes to vascular remodelling. Furthermore, PVAT inflammation triggers MMP activation leading to an increment in transforming growth factor-β production. Vascular injury will downregulate the anti-inflammatory adiponectin in PVAT whereas simultaneously will upregulate the production of proinflammatory adipokines. This pro-inflammatory state promotes the accumulation of macrophages and B/T-cells at the adventitia interface of human aorta, leading to atherosclerosis. PVAT has a very decisive role in the inflammatory response to atherosclerosis (Brown et al., 2014; Henrichot et al., 2005; Takaoka et al., 2010; Kim et al., 2019b). For instance, the differences in PVAT surrounding aorta are important determinants in the distribution of atherosclerosis (Padilla et al., 2013) probably explaining why some arteries are more prone to atherosclerosis than others (Drosos et al., 2016; Akoumianakis et al., 2017). Previous studies transplanted pro-inflammatory adipose tissue to the perivascular area of normal carotid arteries and induced the appearance of atherosclerotic lesions and the increment of inflammation (Henrichot et al., 2005; Öhman et al., 2011). Indeed, dysfunctional PVAT releases pro and anti-inflammatory agents able to influence the establishment and evolution of atherosclerosis (Antonopoulos et al., 2015; Du et al., 2015; Hildebrand et al., 2018; Li et al., 2014). In addition, it was suggested that PVAT oxidative stress may add vascular injury, in apolipoprotein E (ApoE) knockout mice with pronounced atherosclerosis (Li et al., 2013). An increment in PVAT mass and dysfunction is directly implied in inflammation of the adjacent layers of arteries and therefore related with the pathogenesis of atherosclerosis. The expansion of perivascular adipocytes leads to an increment in the production of pro-inflammatory adipocytokines. Cytokines like IL-6 and TNF-α are also produced by macrophages within the adipose tissue. The adipocytokines have a paracrine effect on endothelium causing endothelial dysfunction, hypercoagulability, augmented chemotaxis by upregulation of CCL2 and adhesion of monocytes to the endothelium by amplified expression of adhesion molecules. Those paracrine effects can be exerted directly in the adjacent tissues leading to proliferation of VSMCs and infiltration of macrophages into the artery wall (Verhagen and Visseren, 2011). Various studies have focus on the adipocytokines produced by dysfunctional PVAT and their effects on atherosclerotic progression (Antoniades et al., 2019a). The migration of leucocytes into the vessel wall highlights the involvement of the adventitia in atherosclerosis. Several in vivo studies have shown that application of inflammatory cytokines on coronary arteries increases the leukocyte migration and VSMCs lesions. There is also an arterial remodeling and increase in intima thickness (Libby et al., 2019). CCL2 and IL-8 have been detected in aortic PVAT. PVAT conditioning media cause migration of monocytes, granulocytes and activated T-cell, in vitro. Using an antibody for both CCL2 and IL-8 inhibits the migration of monocytes and the subsequent modifications in the endothelium. These studies have shown that PVAT properties influence the inflammatory process in the vascular wall, a hallmark of the atherosclerotic progress (Henrichot et al., 2005; Karastergiou et al., 2010; Antoniades et al., 2019a, b). The concept of PVAT inflammation inducing atherosclerosis in the underlying vessel is supported by early studies of human abdominal aortic PVAT and epicardial adipose tissue (EAT). The role of EAT in coronary atherosclerosis has been extensively monitored in large epidemiology studies and automated quantification of EAT volume in clinical routine could be a reliable tool for cardiovascular risk assessment (Commandeur et al., 2018). More recently, pericoronary adipose tissue, due to its close proximity to the vasculature was considered as a sensor of coronary inflammation and an important modulator of atherosclerosis (Antoniades et al., 2019a; Libby et al., 2019). Importantly, normal PVAT can also have a protective action against atherosclerosis. Previous studies have shown that PVAT around thoracic aorta (BAT like) plays a crucial protective role in the pathogenesis of atherosclerosis (Chang et al., 2012; Baltieri et al., 2018). Likewise,

2.5. Metabolic disorders Aging is known to increase the prevalence of metabolic disorders like diabetes and its associated vascular complications. The impact of type 2 diabetes in the modulation of PVAT properties remains largely unexplored. It was previously suggested that indirectly, PVAT may regulate insulin resistance and type 2 diabetes by controlling crucial determinants such as muscle perfusion, liver inflammation, insulin secretion, and basal metabolic rate (review by Saxton et al., 2019). Accumulation of intramuscular adipose tissue independently increases the risk of incident of diabetes, demonstrating its relevance for glucose metabolism (Trouwborst et al., 2018). In addition, it was previously described that muscle insulin sensitivity can be regulated by PVAT (Meijer et al., 2013, 2015) in ob/ob diabetic mice. Indeed, insulin signalling pathways are modified in metabolic disorders such as diabetes leading to vascular insulin resistance. In addition, in metabolic diseases, different modifications occur in the vascular wall, due to oxidative stress, inflammation, promoting changes in PVAT phenotype that exacerbate vascular dysfunction. We and other have previously reported an increment in PVAT oxidative stress in animal models of diabetes. In Goto-kakizaki (GK) rats, an animal model of type 2 diabetes, we have previously reported that periaortic adipose tissue displays both oxidative stress and inflammation contributing to an increment in vasoconstriction response and exacerbating endothelial dysfunction (Leandro et al., 2018; Azul et al., 2019). On the other hand, in streptozotocin (STZ)-induced type 1 diabetic rats, it was previously reported an increment in the anticontractile effect in periaortic adipose tissue (Lee et al., 2009). In the same model of type 1 diabetes but in a different location and type of perivascular 7

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et al., 2019). Recently, Elnabawi and co-workers suggested that pericoronary adipose tissue attenuation measured by coronary CT angiography may be used to track response to interventions for coronary artery disease like anti-inflammatory treatments (Elnabawi et al., 2019). Indeed, PVAT imaging represents an attractive method that should be included in clinical risk stratification.

adipose tissue, H2O2 generation is increased in PVAT of skeletal muscle arteries potentiating the vasoconstriction response (Emilova et al., 2016). In addition, mesenteric PVAT from mice with type 1 diabetes is more susceptible to activation of the pro-inflammatory JNK signalling which impairs eNOS activity and reduces adiponectin expression (Nacci et al., 2016). Indeed, several studies have suggested that PVAT (capable of producing anion superoxide, H2O2 and peroxynitrite) exhibits oxidative stress contributing to the vascular dysfunction under diabetic conditions. These studies suggest a pro-inflammatory and pro-oxidant PVAT in small arteries of diabetic mice that indirectly promote insulin resistance (Meijer et al., 2013). On the other hand, thoracic aortic PVAT of the same model of type 1 diabetes exhibits adipocytes with reduced area and an anticontractile phenotype (Lee et al., 2009). The type and location of PVAT depots and the animal models of diabetes used may explain the discrepancies observed with some authors defending a switching from a vasodilatory to a constrictive phenotype under diabetic conditions only in small arteries surrounded by white PVAT in models of type 1 diabetes with no modifications in periaortic adipose depot after 2 weeks of STZ-induced hyperglycaemia. A long-term type 2 diabetic phenotype, as in 8-month-old GK diabetic rats was able to promote dysfunction in periaortic adipose tissue accompanying by concomitant vascular dysfunction (Leandro et al., 2018; Azul et al., 2019). Angiotensin II, phenylephrine and serotonin can increase the release of H2S from periaortic PVAT (Fang et al., 2009). Moreover, cystathionine-γ-lyase-derived H2S is reduced in rats with diabetes (Emilova et al., 2015). In individuals with pre-diabetes and type 2 diabetes, it was previously shown an increased thoracic periaortic adipose tissue volume suggestive of reduced metabolic activity (Yang et al., 2013). In the Framingham study the volumes of thoracic periaortic adipose tissue were associated with visceral adipose tissue depots and with fasting plasma glucose (Lehman et al., 2010) suggesting that a relation between the two adipose tissue depots, notwithstanding the differences between them. Future studies are needed to elucidate the sources of PVAT-derived products in diabetic individuals.

4. Reversing PVAT dysfunction 4.1. Weight loss and bariatric surgery Recent studies have shown that PVAT phenotype is modified following continued weight lost, low calorie diets and after bariatric surgery contributing to the beneficial vascular effects observed under these conditions. Indeed, in obese animal models body weight loss induced by caloric restriction promotes a reduction in adipocytes size, ameliorating PVAT function and reverting hypertension (Bussey et al., 2016). In obese subjects, low caloric diets substantially reduced epicardial fat (Iacobellis et al., 2008). In addition, bariatric surgery was able to reduce PVAT inflammation and restore normal anticontractile PVAT phenotype on human small arteries notwithstanding persistent obesity (Aghamohammadzadeh et al., 2013). Bariatric surgery has also been shown to reduce EAT (Gaborit et al., 2012). 4.2. Physical exercise Exercise is a crucial modulator of cardiometabolic health with relevant pleiotropic properties capable of modulating vascular function. Various studies in humans and in animal models have proved that physical exercise as an anti-inflammatory effect both at vascular level and in different adipose tissue depots (including PVAT). Indeed, aerobic exercise was able to reduce the number and size of adipocytes and improve mitochondrial biogenesis. In trained healthy rats, the expression of eNOS significantly increased in aortic PVAT suggesting a possible mechanism capable of restoring PVAT phenotype in obesity. Indeed, several studies have recently reported that aerobic exercise prevents or restores eNOS activity reverting PVAT dysfunction (Sousa et al., 2019; DeVallance et al., 2019; Meziat et al., 2019). In addition, Ouyang and co-workers have recently shown that chronic exercise training prevents coronary artery stiffening in aortic-banded mini swine by a mechanism that involves advanced glycation end products derived from PVAT (Ouyang et al., 2019).

3. PVAT as an imaging biomarker It was recently shown that imaging PVAT may be used in the clinical practice as a surrogate marker of vascular disease. Antoniades and coworkers developed a novel clinical method for the evaluation of PVAT inflammation (Antoniades et al., 2019a, b). In animal models these studies are performed with ex vivo evaluation of blood vessels in wire myographs. In humans, imaging techniques based on the utilization of an algorithmically derived fat attenuation index (FAI) from computer tomography (CT) coronary angiograms demonstrated the level of lipid accumulation in mature adipocytes next to coronary vessels. The FAI has been validated by Antonopoulos and colleagues at the University of Oxford and used as a marker of vascular inflammation in cardiovascular disease patients (Antonopoulos et al., 2017; Oikonomou et al., 2018). Other imaging techniques are available such as positron emission tomography (PET) imaging, the gold standard in imaging of tissue inflammation in vivo. FDG uptake using PET showed greater standardized uptake value in pericoronary fat to evaluate PVAT inflammation (Ohyama et al., 2017; Mazurek et al., 2017). However, low spatial resolution, high background noise from the myocardial uptake of FDG, high exposure to radiation, and low clinical availability are limiting factors for PET imaging, confining its use in low risk populations. In addition, high-resolution magnetic resonance (MR) imaging of PVAT was used to demonstrate that PVAT mass negatively correlates with insulin sensitivity (Rittig et al., 2008). Evaluation of PVAT around coronary plaques revealed its contribution to the development of atherosclerosis (Goeller et al., 2018; Lin

4.3. Targeting local inflammation It is widely accepted that local inflammation is a risk factor for vascular disease long before its systemic manifestations. Low-grade inflammation and the infiltration of immune cells into vascular wall lead to vascular dysfunction. The inflammatory profile is exacerbated in aging and in several age-related disorders including hypertension and type 2 diabetes. PVAT inflammation is an important surrogate marker of vascular disease highlighting the need to reduce this local inflammatory component in the vasculature (Fig. 4). Inflammation may be reduced with several anti-inflammatory agents with potential beneficial effects at PVAT level (Mikolajczyk et al., 2019). For instance, it was previously shown that TNF-α blockade prevented the PVAT pro-inflammatory profile in type 1 diabetic mice (Nacci et al., 2016). The effects of infliximab, a TNF-α blocking antibody, on PVAT function have been investigated in type 1 diabetic mice (Nacci et al., 2016). In this model, PVAT displayed activation of c-JunN-terminal kinase signalling pathways associated with reduced adiponectin synthesis and dysregulation in adiponectin receptor expression. In addition, eNOS phosphorylation and endothelial function were impaired in mesenteric arteries of STZ-induced diabetic mice (Nacci et al., 2016). However, treatment with infliximab normalized expression of 8

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Fig. 4. Scheme representing some of the signalling pathways that occur associated with PVAT paracrine effects. PVAT is known to have vasoprotective effects through the production of adipokines such as adiponectin in normal health conditions (left panel). Under pathologic conditions PVAT changes its secretome and different amounts of adipokines and chemokines are produced occurring a disruption of the normal physiologic pathways in metabolic syndrome (right panel). ADR1, adiponectin receptor 1; AMPK, adenosine 5′-monophosphate-activated protein kinase; AT 1–7, angiotensin 1–7; AT1, angiotensin receptor 1; BH2, 7,8 dihydrobioterin; BH4, tetrahydrobioterin; BKCa, large-conductance Ca2+-sensitive K+ channels; CCL2, C-C motif chemokine ligand 2; cGMP, cyclic guanosine 3′,5′monophosphate; eNOS, endothelial nitric oxide synthase; ERK1/2, extracellular signal-regulated kinase 1/2; ET1, endothelin 1; FFA, free fatty acids; IL, interleukin; iNOS, inducible nitric oxide synthase; IRS1/2, insulin receptor subtract 1/2; JNK, c-Jun NH2-terminal kinase; NO, nitric oxide; PAME, palmitic acid methyl ester; PGI2, prostacyclin; PKG, protein kinase G; PPARγ, peroxisome proliferator–activated receptor-γ; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; TNF-α, tumour necrosis factor-α.

4.4. Restoring eNOS function

adiponectin and its receptors, and improved eNOS activity. In contrast, obese patients with metabolic syndrome treated with infliximab did not restore the anticontractile effect of PVAT (Greenstein et al., 2009). More studies in humans are necessary to elucidate the role of TNF αtargeting therapy in this context. Recently, AVE0991, a specific agonist of Mas receptor, reduced monocyte/macrophage recruitment and differentiation to PVAT during initial stages of atherosclerosis in ApoE-/- mice highlighting the antiinflammatory and anti-atherosclerotic properties of this compound (Skiba et al., 2017). PVAT secretes and is influenced by dipeptidyl peptidase-IV (DPPIV), known to exert several deleterious effects on the vasculature (Akoumianakis and Antoniades, 2017). Salim and co-workers have reported that teneligliptin (a DPP-IV inhibitor) ameliorated PVAT phenotype in a model of normoglycaemic ApoE-/- mice due to its antiinflammatory, antioxidant properties in both the vasculature and PVAT leading to reduced atherosclerosis (Salim et al., 2017). In addition, other anti-diabetic drugs such as metformin or agonists of glucagon-like peptide-1 (GLP-1) displayed an anti-inflammatory that could potential target the inflammation observed in PVAT (Sena et al., 2011; Lee and Jun, 2016; Elkhatib et al., 2019). In addition, it was also suggested that prevention of mineralocorticoid receptor activation and therapeutically effective approaches able to reduce PVAT inflammasome could be alternative strategies (Jia et al., 2017).

Caloric restriction and bariatric surgery (Bussey et al., 2016; Aghamohammadzadeh et al., 2013) can restore eNOS expression in PVAT improving NO bioavailability. Importantly, Xia et al. (2017) treating obese mice with WS® 1442, a compound that restores eNOS function (Xia et al., 2017), reverted periaortic adipose tissue dysfunction independent of fat mass (Xia et al., 2017), confirming the importance of akt-eNOS signalling pathway in PVAT function (Xia and Li, 2017).

4.5. Stimulating H2S production in PVAT Enhancing H2S production in PVAT may represent another promising target. H2S production was reduced and PVAT anticontractile function was lost in the aorta of cafeteria-diet-fed rats (Bełtowski, 2013). Moreover, treatment with the anti-diabetic drug rosiglitazone restored cystathionine-γ-lyase activity, and subsequently increased H2S production and restored PVAT function. Similarly, atorvastatin has been shown to increase H2S production and enhance the phenylephrine induced PVAT anticontractile effect in healthy rat aortas (Wójcicka et al., 2011). Indeed, previous studies have suggested that statins provide a paradigm for the development of new therapeutic agents aimed at modulating PVAT function (Sanna et al., 2017) and modulation of EAT (Alexopoulos et al., 2013). 9

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activity of type 2 innate lymphoid cells, respectively. In consequence, there is a polarization of adipose tissue macrophages towards the antiinflammatory M2 phenotype that contribute to the beiging of WAT. BAT activation and WAT beiging protect against several risk factors such as obesity, hypertension, diabetes, dyslipidemia and ultimately may restore the physiological function of adipose tissue and other metabolically important tissues and organs (Saxton et al., 2019).

4.6. AMPK activators Resveratrol, genistein, calycosin, salicylate, 5-aminoimidazole-4carboxamide ribonucleotide (AICAR), metformin or diosgenin are adenosine 5′-monophosphate-activated protein kinase (AMPK) activators known to reduce the inflammatory profile in PVAT and increment eNOS phosphorylation and PVAT function (Sun et al., 2014; Chen et al., 2016; Simperova et al., 2016; Han et al., 2018). Incubation of isolated rat PVAT with activators of AMPK increases eNOS phosphorylation and adiponectin secretion and reduces expression of pro-inflammatory cytokines TNF-α, CCL2, and IL-6 (Chen et al., 2016; Sun et al., 2014). In addition, incubation of PVAT with AMPK activators before applying the PVAT to isolated aortic rings improved acetylcholine-induced vasodilation. Oral administration of AMPK activators reduced aortic PVAT mass and improved responsiveness of the aorta to acetylcholine (Chen et al., 2016; Sun et al., 2014). Antidiabetic agents such as the GLP-1 analogue liraglutide ameliorated vascular dysfunction through a cAMP-independent PKA-AMPK pathway in PVAT of obese animal models (Han et al., 2019). In addition, calycosin, a bioactive isoflavonoid, was shown to protect endothelial function through a mechanism that upregulates the adiponectin/AMPK/eNOS pathway in PVAT of obese mice (Han et al., 2018). Taken together, these studies suggest that targeting AMPK may also be therapeutically useful in obesity and other metabolic disorders (Fig. 4).

4.8. Manipulating secretome (adipokines/chemokines) Several therapeutic approaches have already been used to manipulate PVAT secretome with beneficial effects on vascular function. Namely, dietary restriction, bariatric surgery, physical activity, metformin, rosiglitazone and statin therapies (the latest through and increment in H2S production), DPP4 inhibitors, melatonin, anti-inflammatory agents. The metabolism of PVAT is linked to its secretory function (Min et al., 2016). BAT produces specific products including fibroblast growth factor 21, endocannabinoids, and adiponectin that regulate metabolism and function of other organs (Kajimura et al., 2015; Berti et al., 2016; Villarroya et al., 2017a, 2017b). Stimulating adipose tissue metabolism by β-adrenergic agonists enhances adiponectin secretion (Min et al., 2016), showing that the metabolic and secretory functions of adipose tissue are regulated by shared mechanisms. PVAT releases adiponectin when the pathway eNOS-NO-cGMP-PKG is stimulated (Withers et al., 2014). We have previously demonstrated that treatment with exogenous adiponectin improved the pro-inflammatory PVAT phenotype present in 12-month old Wistar rats fed with high fat diet. Concomitantly, this effect was accompanied by an increment in eNOS phosphorylation and a decrement in oxidative stress, normalizing endothelial dysfunction in mesenteric arteries of this animal model (Sena et al., 2017). In addition, it was previously shown that statins increment systemic levels of adiponectin (Katsiki and Mantzoros, 2016). Peroxisome proliferator-activated receptor-γ agonists such as glitazones and AMPK activators are also able to stimulate adiponectin release (Fig. 4). Thus, therapeutic approaches that promote an increment in adiponectin are potentially useful and must be further evaluated in clinical trials. In addition, reducing the pro-inflammatory, pro-contractile factors is another therapeutic alternative.

4.7. Inducing the beiging in PVAT Therapeutic interventions that promote the beiging of white adipose tissue and/or activate endogenous BAT may improve metabolic health. BAT transplantation and cold-induced adipose tissue promote an enhancement of leptin and adiponectin levels and its paracrine actions. Leptin reduces inflammation in adipocytes via insulin-like growth factor 1. Adiponectin promotes thermogenesis and induces vasorelaxation and has anti-inflammatory properties via the increment in the proliferation of M2 macrophages. Hui et al. (2015) reported that cold exposure increments the population of M2 macrophages alone without changing the number of pro-inflammatory M1 macrophages. Indeed, M2 macrophages within an inflamed adipose tissue can be protective by effectively reducing the percentage of M1 macrophages within the total adipose tissue macrophage population. Notably, in healthy adipose tissue, M2 macrophages are more abundant than M1 macrophages (Lumeng et al., 2007), the latter being the main source of TNF-α (Usher et al., 2010). Other studies have found that cold exposure and β3 adrenergic receptor-mediated BAT activation enhances the selective uptake of fatty acids and ultimately accelerating the hepatic removal of the cholesterol-enriched remnants and protecting from atherosclerosis (Berbée et al., 2015). It was recent shown that a decrease in PVAT browning with aging leads to an attenuated anticontractile effect on the thoracic aorta in spontaneously hypertensive rats (Kong et al., 2018). This study reported that azilsartan mediated inhibition of AT1 in PVAT induces decreased mesenteric PVAT browning, which results in loss of a compensatory effect of PVAT in SHRSP.ZF rats with metabolic syndrome. Overexpression of mitoNEET in adipocytes induces browning (Kusminski et al., 2014). Pioglitazone, an insulin sensitizer that can bind mitoNEET, induced a reduction in PVAT inflammation and fibrosis, resulting in inhibition of arterial stiffness progression (Chang et al., 2018) and improved vascular function (Quesada et al., 2018). Perivascular inflammation and modified immune cell phenotype, can precede the development of several metabolic disorders (El Assar et al., 2016). Thus, therapeutic manipulation of the immune system is crucial and induces the beiging of adipose tissue. Recent studies have described that cold exposure and helminth infection instigate interleukin (IL)-4 secretion from eosinophils, and IL-33, which promotes the

5. Conclusion and future perspectives PVAT is a major regulator of vascular function in health and disease. Despite the recent advances in this field, the limitations of current experimental models present many gaps in knowledge. The mechanisms that regulate perivascular adipocyte phenotype changes and communication with other cell types (ie, inflammatory cells, nerve cells, progenitor cells) and their impact on age-related vascular disease remain unknown. Establishing more and better animal models of disease is crucial to answer these questions in the future. Research involving immune–PVAT interactions is limited in aging and age-related diseases and should be further developed in order to clarify the mechanisms involved and identify novel therapeutic targets. Indeed, PVAT may be considered a predictor of vascular disease and a potential therapeutic target in aging vessels that deserves further investigation. Acknowledgment This work was supported by the Fundação para a Ciência e a Tecnologia, Portugal: PTDC/BIM-MET/4447/2014; POCI-01-0145FEDER-016784. References Abu Bakar, H., Robert Dunn, W., Daly, C., Ralevic, V., 2017. Sensory innervation of perivascular adipose tissue: a crucial role in artery vasodilatation and leptin release.

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targeted proteomics approach. Arch. Physiol. Biochem. 122, 281–288. https://doi. org/10.1080/13813455.2016.1212898. Blirando, K., 2016. Epigenetic regulation of adipocytes phenotype: implication for perivascular adipose tissue contribution to cardiometabolic diseases. Adipobiology 8, 19–34. https://doi.org/10.14748/adipo.v8.2090. Brown, N.K., Zhou, Z., Zhang, J., Zeng, R., Wu, J., Eitzman, D.T., Chen, Y.E., Chang, L., 2014. Perivascular adipose tissue in vascular function and disease: a review of current research and animal models. Arterioscler. Thromb. Vasc. Biol. 34, 1621–1630. https://doi.org/10.1161/ATVBAHA.114.303029. Bulloch, J.M., Daly, C.J., 2014. Autonomic nerves and perivascular fat: interactive mechanisms. Pharmacol. Ther. 143, 61–73. https://doi.org/10.1016/j.pharmthera. 2014.02.005. Bussey, C.E., Withers, S.B., Aldous, R.G., Edwards, G., Heagerty, A.M., 2016. Obesityrelated perivascular adipose tissue damage is reversed by sustained weight loss in the rat. Arterioscler. Thromb. Vasc. Biol. 36, 1377–1385. https://doi.org/10.1161/ ATVBAHA.116.307210. Chang, L., Villacorta, L., Li, R., Hamblin, M., Xu, W., Dou, C., Zhang, J., Wu, J., Zeng, R., Chen, Y.E., 2012. Loss of perivascular adipose tissue on peroxisome proliferator–activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. Circulation 126, 1067–1078. https://doi.org/10.1161/CIRCULATIONAHA.112.104489. Chang, L., Xiong, W., Zhao, X., Fan, Y., Guo, Y., Garcia-Barrio, M., Zhang, J., Jiang, Z., Lin, J.D., Chen, Y.E., 2018. Bmal1 in perivascular adipose tissue regulates restingphase blood pressure through transcriptional regulation of angiotensinogen. Circulation 138, 67–79. https://doi.org/10.1161/CIRCULATIONAHA.117.029972. Chen, J.Y., Tsai, P.J., Tai, H.C., Tsai, R.L., Chang, Y.T., Wang, M.C., Chiou, Y.W., Yeh, M.L., Tang, M.J., Lam, C.F., Shiesh, S.C., 2013. Increased aortic stiffness and attenuated lysyl oxidase activity in obesity. Arterioscler. Thromb. Vasc. Biol. 33, 839–846. https://doi.org/10.1161/ATVBAHA.112.300036. Chen, Y., Xu, X., Zhang, Y., Liu, K., Huang, F., Liu, B., Kou, J., 2016. Diosgenin regulates adipokine expression in perivascular adipose tissue and ameliorates endothelial dysfunction via regulation of AMPK. J. Steroid Biochem. Mol. Biol. 155, 155–165. https://doi.org/10.1016/j.jsbmb.2015.07.005. Chirinos, J.A., Segers, P., Hughes, T., Townsend, R., 2019. Large-artery stiffness in health and disease. J. Am. Coll. Cardiol. 74, 1237–1263. https://doi.org/10.1016/j.jacc. 2019.07.012. Commandeur, F., Goeller, M., Betancur, J., Cadet, S., Doris, M., Chen, X., Berman, D.S., Slomka, P.J., Tamarappoo, B.K., Dey, D., 2018. Deep learning for quantification of epicardial and thoracic adipose tissue from non-contrast CT. IEEE Trans. Med. Imaging 37, 1835–1846. https://doi.org/10.1109/TMI.2018.2804799. Darios, E., Winner, B., Charvat, T., Krasinksi, A., Punna, S., Watts, S., 2016. The adipokine chemerin amplifies electrical field-stimulated contraction in the isolated rat superior mesenteric artery. Am. J. Physiol. Heart Circ. Physiol. 311, H498–H507. https://doi. org/10.1152/ajpheart.00998.2015. DeVallance, E., Branyan, K.W., Lemaster, K.C., Anderson, R., Marshall, K.L., Olfert, I.M., Smith, D.M., Kelley, E.E., Bryner, R.W., Frisbee, J.C., Chantler, P.D., 2019. Exercise training prevents the perivascular adipose tissue-induced aortic dysfunction with metabolic syndrome. Redox Biol. 26, 101285. https://doi.org/10.1016/j.redox.2019. 101285. Doderer, S.A., Gäbel, G., Kokje, V.B., Northoff, B.H., Holdt, L.M., Hamming, J.F., Lindeman, J.H., 2018. Adventitial adipogenic degeneration is an unidentified contributor to aortic wall weakening in the abdominal aortic aneurysm. J. Vasc. Surg. 67, 1891–1900. https://doi.org/10.1016/j.jvs.2017.05.088. Donato, A.J., Machin, D.R., Lesniewski, L.A., 2018. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ. Res. 123, 825–848. https:// doi.org/10.1161/CIRCRESAHA.118.312563. Drosos, I., Chalikias, G., Pavlaki, M., Kareli, D., Epitropou, G., Bougioukas, G., Mikroulis, D., Konstantinou, F., Giatromanolaki, A., Ritis, K., Munzel, T., Tziakas, D., Konstantinides, S., Schafer, K., 2016. Differences between perivascular adipose tissue surrounding the heart and the internal mammary artery: possible role for the leptininflammation-fibrosis-hypoxia axis. Clin. Res. Cardiol. 105, 887–900. https://doi. org/10.1007/s00392-016-0996-7. Du, B., Ouyang, A., Eng, J.S., Fleenor, B.S., 2015. Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in low-density lipoprotein receptor deficient mice. Am. J. Physiol. 308, H1382–H1390. https://doi.org/10.1152/ajpheart. 00712.2014. Eghbalieh, S.D., Chowdhary, P., Muto, A., Ziegler, K.R., Kudo, F.A., Pimiento, J.M., Mirmehdi, I., Model, L.S., Kondo, Y., Nishibe, T., Dardik, A., 2012. Age-related neointimal hyperplasia is associated with monocyte infiltration after balloon angioplasty. J. Gerontol. A Biol. Sci. Med. Sci. 67, 109–117. https://doi.org/10.1093/ gerona/glr190. El Assar, M., Angulo, J., Santos‐Ruiz, M., Ruiz de Adana, J.C., Pindado, M.L., Sánchez‐Ferrer, A., Hernández, A., Rodríguez‐Mañas, L., 2016. Asymmetric dimethylarginine (ADMA) elevation and arginase up‐regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans. J. Physiol. (Paris) 594, 3045–3060. https://doi.org/10.1113/JP271836. Elkhatib, M.A.W., Mroueh, A., Rafeh, R.W., Sleiman, F., Fouad, H., Saad, E.I., Fouda, M.A., Elgaddar, O., Issa, K., Eid, A.H., Eid, A.A., Abd-Elrahman, K.S., El-Yazbi, A.F., 2019. Amelioration of perivascular adipose inflammation reverses vascular dysfunction in a model of nonobese prediabetic metabolic challenge: potential role of antidiabetic drugs. Transl. Res. S1931–5244, 30144–30146. https://doi.org/10. 1016/j.trsl.2019.07.009. Elnabawi, Y.A., Oikonomou, E.K., Dey, A.K., Mancio, J., Rodante, J.A., Aksentijevich, M., Choi, H., Keel, A., Erb-Alvarez, J., Teague, H.L., Joshi, A.A., Playford, M.P., Lockshin, B., Choi, A.D., Gelfand, J.M., Chen, M.Y., Bluemke, D.A., Shirodaria, C., Antoniades, C., Mehta, N.N., 2019. Association of biologic therapy with coronary inflammation in

Cardiovasc. Res. 113, 962–972. https://doi.org/10.1093/cvr/cvx062. Agabiti-Rosei, C., Favero, G., De Ciuceis, C., Rossini, C., Porteri, E., Rodella, L.F., Franceschetti, L., Maria Sarkar, A., Agabiti-Rosei, E., Rizzoni, D., Rezzani, R., 2017. Effect of long-term treatment with melatonin on vascular markers of oxidative stress/ inflammation and on the anticontractile activity of perivascular fat in aging mice. Hypertens. Res. 40, 41–50. https://doi.org/10.1038/hr.2016.103. Agabiti-Rosei, C., Paini, A., De Ciuceis, C., Withers, S., Greenstein, A., Heagerty, A.M., Rizzoni, D., 2018. Modulation of vascular reactivity by perivascular adipose tissue (PVAT). Curr. Hypertens. Rep. 20, 44. https://doi.org/10.1007/s11906-018-0835-5. Aggarwal, S., Qamar, A., Sharma, V., Sharma, A., 2011. Abdominal aortic aneurysm: a comprehensive review. Exp. Clin. Cardiol. 16, 11–15 PMCID: PMC3076160. Aghamohammadzadeh, R., Greenstein, A.S., Yadav, R., Jeziorska, M., Hama, S., Soltani, F., Pemberton, P.W., Ammori, B., Malik, R.A., Soran, H., Heagerty, A.M., 2013. Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity. J. Cardiovasc. Manag. 62, 128–135. https://doi. org/10.1016/j.jacc.2013.04.027. Akoumianakis, I., Antoniades, C., 2017. Dipeptidyl peptidase IV inhibitors as novel regulators of vascular disease. Vascul. Pharmacol. 96–98, 1–4. https://doi.org/10.1016/ j.vph.2017.07.001. Akoumianakis, I., Tarun, A., Antoniades, C., 2017. Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets. Br. J. Pharmacol. 174, 3411–3424. https://doi.org/10.1111/bph.13666. Aldiss, P., Davies, G., Woods, R., Budge, H., Sacks, H.S., Symonds, M.E., 2017. ‘Browning’ the cardiac and peri-vascular adipose tissues to modulate cardiovascular risk. Int. J. Cardiol. 228, 265–274. https://doi.org/10.1016/j.ijcard.2016.11.074. Alexopoulos, N., Melek, B.H., Arepalli, C.D., Hartlage, G.R., Chen, Z., Kim, S., Stillman, A.E., Raggi, P., 2013. Effect of intensive versus moderate lipid-lowering therapy on epicardial adipose tissue in hyperlipidemic post-menopausal women: a substudy of the BELLES trial (Beyond Endorsed Lipid Lowering with EBT Scanning). J. Am. Coll. Cardiol. 61, 1956–1961. https://doi.org/10.1016/j.jacc.2012.12.051. AlGhatrif, M., Strait, J.B., Morrell, C.H., Canepa, M., Wright, J., Elango, P., Scuteri, A., Najjar, S.S., Ferrucci, L., Lakatta, E.G., 2013. Longitudinal trajectories of arterial stiffness and the role of blood pressure: the Baltimore Longitudinal Study of Aging. Hypertension 62, 934–941. https://doi.org/10.1161/HYPERTENSIONAHA.113. 01445. Antoniades, C., Kotanidis, C.P., Berman, D.S., 2019a. Atherosclerosis affecting fat: what can we learn by imaging perivascular adipose tissue? J. Cardiovasc. Comput. Tomogr. https://doi.org/10.1016/j.jcct.2019.03.006. pii: S1934-5925(18)30618-X. Antoniades, C., Antonopoulos, A.S., Deanfield, J., 2019b. Imaging residual inflammatory cardiovascular risk. Eur. Heart J. https://doi.org/10.1093/eurheartj/ehz474. pii: ehz474. Antonopoulos, A.S., Margaritis, M., Coutinho, P., Digby, J., Patel, R., Psarros, C., Ntusi, N., Karamitsos, T.D., Lee, R., De Silva, R., Petrou, M., 2014. Reciprocal effects of systemic inflammation and brain natriuretic peptide on adiponectin biosynthesis in adipose tissue of patients with ischemic heart disease. Arterioscler. Thromb. Vasc. Biol. 34, 2151–2159. https://doi.org/10.1161/ATVBAHA.114.303828. Antonopoulos, A.S., Margaritis, M., Coutinho, P., Shirodaria, C., Psarros, C., Herdman, L., Sanna, F., De Silva, R., Petrou, M., Sayeed, R., Krasopoulos, G., 2015. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. Diabetes 64, 2207–2219. https://doi.org/10.2337/db14-1011. Antonopoulos, A.S., Sanna, F., Sabharwal, N., Thomas, S., Oikonomou, E.K., Herdman, L., Margaritis, M., Shirodaria, C., Kampoli, A.M., Akoumianakis, I., Petrou, M., 2017. Detecting human coronary inflammation by imaging perivascular fat. Sci. Transl. Med. 9https://doi.org/10.1126/scitranslmed.aal2658. p.eaal2658. Aroor, A.R., Jia, G., Sowers, J.R., 2017. Cellular mechanisms underlying obesity-induced arterial stiffness. Am. J. Physiol. 314, R387–R398. https://doi.org/10.1152/ajpregu. 00235.2016. Ayala-Lopez, N., Jackson, W.F., Burnett, R., Wilson, J.N., Thompson, J.M., Watts, S.W., 2015. Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue. Am. J. Physiol. Heart Circ. Physiol. 309, H1904–H1914. https://doi.org/10.1152/ajpheart.00308.2015. Azul, L., Leandro, A., Boroumand, P., Klip, A., Seiça, R., Sena, C.M., 2019. Increased inflammation, oxidative stress and a reduction in antioxidant defense enzymes in perivascular adipose tissue contribute to vascular dysfunction in type 2 diabetes. Free Radic. Biol. Med. https://doi.org/10.1016/j.freeradbiomed.2019.11.002. Bailey-Downs, L.C., Tucsek, Z., Toth, P., Sosnowska, D., Gautam, T., Sonntag, W.E., Csiszar, A., Ungvari, Z., 2012. Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation. J. Gerontol. A Biol. Sci. Med. Sci. 68, 780–792. https://doi.org/10.1093/gerona/gls238. Baltieri, N., Guizoni, D.M., Victorio, J.A., Davel, A.P., 2018. Protective role of perivascular adipose tissue in endothelial dysfunction and insulin induced vasodilatation of hypercholesterolemic LDL receptor deficient mice. Front. Physiol. 9, 229. https://doi. org/10.3389/fphys.2018.00229. Bełtowski, J., 2013. Endogenous hydrogen sulfide in perivascular adipose tissue: role in the regulation of vascular tone in physiology and pathology. Can. J. Physiol. Pharmacol. 91, 889–898. https://doi.org/10.1139/cjpp-2013-0001. Berbée, J.F., Boon, M.R., Khedoe, P.P.S., Bartelt, A., Schlein, C., Worthmann, A., Kooijman, S., Hoeke, G., Mol, I.M., John, C., Jung, C., 2015. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat. Commun. 6, 6356. https://doi.org/10.1038/ncomms7356. Berti, L., Hartwig, S., Irmler, M., Rädle, B., Siegel-Axel, D., Beckers, J., Lehr, S., Al-Hasani, H., Häring, H.U., Hrabě de Angelis, M., Staiger, H., 2016. Impact of fibroblast growth factor 21 on the secretome of human perivascular preadipocytes and adipocytes: a

11

Ageing Research Reviews 59 (2020) 101040

M. Queiroz and C.M. Sena

109537. https://doi.org/10.1016/j.biopha.2019.109537. Hashimoto, K., Kugo, H., Tanaka, H., Iwamoto, K., Miyamoto, C., Urano, T., Unno, N., Hayamizu, K., Zaima, N., Moriyama, T., 2018. The effect of a high-fat diet on the development of abdominal aortic aneurysm in a vascular hypoperfusion-induced animal model. J. Vasc. Res. 55, 63–74. https://doi.org/10.1159/000481780. Henrichot, E., Juge-Aubry, C.E., Pernin, A., Pache, J.C., Velebit, V., Dayer, J.M., Meda, P., Chizzolini, C., Meier, C.A., 2005. Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of atherosclerosis? Arterioscler. Thromb. Vasc. Biol. 25, 2594–2599. https://doi.org/10.1161/01.ATV.0000188508.40052.35. Higashi, Y., Sukhanov, S., Anwar, A., Shai, S.Y., Delafontaine, P., 2012. Aging, atherosclerosis, and IGF-1. J. Gerontol. A Biol. Sci. Med. Sci. 67, 626–639. https://doi.org/ 10.1093/gerona/gls102. Hildebrand, S., Stümer, J., Pfeifer, A., 2018. PVAT and its relation to brown, beige, and white adipose tissue in development and function. Front. Physiol. 9, 70. https://doi. org/10.3389/fphys.2018.00070. Hui, X., Gu, P., Zhang, J., Nie, T., Pan, Y., Wu, D., Feng, T., Zhong, C., Wang, Y., Lam, K.S., Xu, A., 2015. Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab. 22, 279–290. https:// doi.org/10.1016/j.cmet.2015.06.004. Iacobellis, G., Singh, N., Wharton, S., Sharma, A.M., 2008. Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Obesity 16, 1693–1697. https://doi.org/10.1038/oby.2008.251. Jia, G., Aroor, A.R., Sowers, J.R., 2017. The role of mineralocorticoid receptor signaling in the cross-talk between adipose tissue and the vascular wall. Cardiovasc. Res. 113, 1055–1063. https://doi.org/10.1093/cvr/cvx097. Kajimura, S., Spiegelman, B.M., Seale, P., 2015. Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 22, 546–559. https://doi.org/10.1016/j.cmet. 2015.09.007. Karastergiou, K., Evans, I., Ogston, N., Miheisi, N., Nair, D., Kaski, J.C., Jahangiri, M., Mohamed-Ali, V., 2010. Epicardial adipokines in obesity and coronary artery disease induce atherogenic changes in monocytes and endothelial cells. Arterioscler. Thromb. Vasc. Biol. 30, 1340–1346. https://doi.org/10.1161/ATVBAHA.110.204719. Katsiki, N., Mantzoros, C.S., 2016. Statins in relation to adiponectin: a significant association with clinical implications. Atherosclerosis 253, 270–272. https://doi.org/10. 1016/j.atherosclerosis.2016.08.009. Kiefer, F.W., Cohen, P., Plutzky, J., 2012. Fifty shades of brown: perivascular fat, thermogenesis, and atherosclerosis. Circulation 126, 1012–1015. https://doi.org/10. 1161/CIRCULATIONAHA.112.123521. Kim, H.W., Belin de Chantemèle, E.J., Weintraub, N.L., 2019a. Perivascular adipocytes in vascular disease. Arterioscler. Thromb. Vasc. Biol. 39, 2220–2227. https://doi.org/ 10.1161/ATVBAHA.119.312304. Kim, S., Lee, E.S., Lee, S.W., Kim, Y.H., Lee, C.H., Jo, D.G., Kim, S.H., 2019b. Site-specific impairment of perivascular adipose tissue on advanced atherosclerotic plaques using multimodal nonlinear optical imaging. Proc. Natl. Acad. Sci. U.S.A. 116, 17765–17774. https://doi.org/10.1073/pnas.1902007116. Kong, L.R., Zhou, Y.P., Chen, D.R., Ruan, C.C., Gao, P.J., 2018. Decrease of perivascular adipose tissue browning is associated with vascular dysfunction in spontaneous hypertensive rats during aging. Front. Physiol. 9, 400. https://doi.org/10.3389/fphys. 2018.00400. Krueger, F., Kappert, K., Foryst-Ludwig, A., Kramer, F., Clemenz, M., Grzesiak, A., Sommerfeld, M., Paul Frese, J., Greiner, A., Kintscher, U., Unger, T., 2017. AT1-receptor blockade attenuates outward aortic remodeling associated with diet-induced obesity in mice. Clin. Sci. 131, 1989–2005. https://doi.org/10.1042/CS20170131. Kugo, H., Tanaka, H., Moriyama, T., Zaima, N., 2018. Pathological implication of adipocytes in AAA development and the rupture. Ann. Vasc. Dis. 11, 159–168. https:// doi.org/10.3400/avd.ra.17-00130. Kugo, H., Moriyama, T., Zaima, N., 2019. The role of perivascular adipose tissue in the appearance of ectopic adipocytes in the abdominal aortic aneurysmal wall. Adipocyte 8, 229–239. https://doi.org/10.1080/21623945.2019.1636625. Kurobe, H., Hirata, Y., Matsuoka, Y., Sugasawa, N., Higashida, M., Nakayama, T., Maxfield, M.W., Yoshida, Y., Shimabukuro, M., Kitagawa, T., Sata, M., 2013. Protective effects of selective mineralocorticoid receptor antagonist against aortic aneurysm progression in a novel murine model. J. Surg. Res. 185, 455–462. https:// doi.org/10.1016/j.jss.2013.05.002. Kusminski, C.M., Park, J., Scherer, P.E., 2014. MitoNEET-mediated effects on browning of white adipose tissue. Nat. Commun. 5, 3962. https://doi.org/10.1038/ncomms4962. Lakatta, E.G., Levy, D., 2003. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a “set up” for vascular disease. Circulation 107, 139–146. https://doi.org/10.1161/01.CIR.0000048892.83521.58. Laurent, S., Cockcroft, J., Van Bortel, L., Boutouyrie, P., Giannattasio, C., Hayoz, D., Pannier, B., Vlachopoulos, C., Wilkinson, I., Struijker-Boudier, H., 2006. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur. Heart J. 27, 2588–2605. https://doi.org/10.1093/eurheartj/ehl254. Leandro, A., Azul, L., Fernandes, R., Seiça, R., Sena, C., 2018. Contribution of perivascular adipose tissue to vascular dysfunction in type 2 diabetes. Free Radic. Biol. Med. 120, S162. https://doi.org/10.1016/j.freeradbiomed.2018.04.533. Lee, Y.S., Jun, H.S., 2016. Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. Mediators Inflamm. 2016, 3094642. https://doi.org/10.1155/2016/ 3094642. Lee, R.M., Lu, C., Su, L.Y., Gao, Y.J., 2009. Endothelium-dependent relaxation factor released by perivascular adipose tissue. J. Hypertens. 27, 782–790. https://doi.org/ 10.1097/HJH.0b013e328324ed86. Lee, Y.C., Chang, H.H., Chiang, C.L., Liu, C.H., Yeh, J.I., Chen, M.F., Chen, P.Y., Kuo, J.S., Lee, T.J., 2011. Role of perivascular adipose tissue–derived methyl palmitate in vascular tone regulation and pathogenesis of hypertension. Circulation 124, 1160–1171. https://doi.org/10.1161/CIRCULATIONAHA.111.027375.

patients with psoriasis as assessed by perivascular fat attenuation index association of biologic therapy with coronary inflammation in psoriasis association of biologic therapy with coronary inflammation in psoriasis. JAMA Cardiol. https://doi.org/10. 1001/jamacardio.2019.2589. Emilova, R., Dimitrova, D., Mladenov, M., Daneva, T., Schubert, R., Gagov, H., 2015. Cystathionine gamma-lyase of perivascular adipose tissue with reversed regulatory effect in diabetic rat artery. Biotechnol. Biotechnol. Equip. 29, 147–151. https://doi. org/10.1080/13102818.2014.991565. Emilova, R., Dimitrova, D.Z., Mladenov, M., Hadzi-Petrushev, N., Daneva, T., Padeshki, P., Schubert, R., Chichova, M., Lubomirov, L., Simeonovska-Nikolova, D., Gagov, H., 2016. Diabetes converts arterial regulation by perivascular adipose tissue from relaxation into H2O2-Mediated Contraction. Physiol. Res. 65, 799–807. Fang, L., Zhao, J., Chen, Y., Ma, T., Xu, G., Tang, C., Liu, X., B, Geng, 2009. Hydrogen sulfide derived from periadventitial adipose tissue is a vasodilator. J. Hypertens. 27, 2174–2185. https://doi.org/10.1097/HJH.0b013e328330a900. Fernández‐Alfonso, M.S., Somoza, B., Tsvetkov, D., Kuczmanski, A., Dashwood, M., Gil‐Ortega, M., 2018. Role of perivascular adipose tissue in health and disease. Compr. Physiol. 8, 23–59. https://doi.org/10.1002/cphy.c170004. Fésüs, G., Dubrovska, G., Gorzelniak, K., Kluge, R., Huang, Y., Luft, F.C., Gollasch, M., 2007. Adiponectin is a novel humoral vasodilator. Cardiovasc. Res. 75, 719–727. https://doi.org/10.1016/j.cardiores.2007.05.025. Finkel, T., Holbrook, N.J., 2000. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247. https://doi.org/10.1038/35041687. Fitzgibbons, T.P., Kogan, S., Aouadi, M., Hendricks, G.M., Straubhaar, J., Czech, M.P., 2011. Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation. Am. J. Physiol. Heart Circ. Physiol. 301, H1425–H1437. https://doi.org/10.1152/ajpheart.00376.2011. Fleenor, B.S., Eng, J.S., Sindler, A.L., Pham, B.T., Kloor, J.D., Seals, D.R., 2014. Superoxide signaling in perivascular adipose tissue promotes age‐related artery stiffness. Aging Cell 13, 576–578. https://doi.org/10.1111/acel.12196. Folkesson, M., Vorkapic, E., Gulbins, E., Japtok, L., Kleuser, B., Welander, M., Länne, T., Wågsäter, D., 2016. Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms. J. Vasc. Surg. 65, 1171–1179. https://doi.org/10.1016/j.jvs.2015.12.056. Fu, M., Xu, L., Chen, X., Han, W., Ruan, C., Li, J., Cai, C., Ye, M., Gao, P., 2019. Neural crest cells differentiate into brown adipocytes and contribute to periaortic arch adipose tissue formation. Arterioscler. Thromb. Vasc. Biol. 39, 1629–1644. https://doi. org/10.1161/ATVBAHA.119.312838. Gaborit, B., Jacquier, A., Kober, F., Abdesselam, I., Cuisset, T., Boullu-Ciocca, S., Emungania, O., Alessi, M.C., Clément, K., Bernard, M., Dutour, A., 2012. Effects of bariatric surgery on cardiac ectopic fat: lesser decrease in epicardial fat compared to visceral fat loss and no change in myocardial triglyceride content. J. Am. Coll. Cardiol. 60, 1381–1389. https://doi.org/10.1016/j.jacc.2012.06.016. Gao, Y.J., 2007. Dual modulation of vascular function by perivascular adipose tissue and its potential correlation with adiposity/lipoatrophy-related vascular dysfunction. Curr. Pharm. Des. 13, 2185–2192. https://doi.org/10.2174/138161207781039634. Gao, Y.J., Zeng, Z.H., Teoh, K., Sharma, A.M., Abouzahr, L., Cybulsky, I., Lamy, A., Semelhago, L., Lee, R.M., 2005. Perivascular adipose tissue modulates vascular function in the human internal thoracic artery. J. Thorac. Cardiovasc. Surg. 130, 1130–1136. https://doi.org/10.1016/j.jtcvs.2005.05.028. Goeller, M., Achenbach, S., Cadet, S., Kwan, A.C., Commandeur, F., Slomka, P.J., Gransar, H., Albrecht, M.H., Tamarappoo, B.K., Berman, D.S., Marwan, M., Dey, D., 2018. Pericoronary adipose tissue computed tomography attenuation and high-risk plaque characteristics in acute coronary syndrome compared with stable coronary artery disease. JAMA Cardiol. 3, 858–863. https://doi.org/10.1001/jamacardio.2018.1997. Gollasch, M., 2017. Adipose-vascular coupling and potential therapeutics. Annu. Rev. Pharmacol. Toxicol. 57, 417–436. https://doi.org/10.1146/annurev-pharmtox010716-104542. Gräbner, R., Lötzer, K., Döpping, S., Hildner, M., Radke, D., Beer, M., Spanbroek, R., Lippert, B., Reardon, C.A., Getz, G.S., Fu, Y.X., Hehlgans, T., Mebius, R.E., van der Wall, M., Kruspe, D., Englert, C., Lovas, A., Hu, D., Randolph, G.J., Weih, F., Habenicht, A.J., 2009. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J. Exp. Med. 206, 233–248. https://doi.org/10.1084/jem.20080752. Greenstein, A.S., Khavandi, K., Withers, S.B., Sonoyama, K., Clancy, O., Jeziorska, M., Laing, I., Yates, A.P., Pemberton, P.W., Malik, R.A., Heagerty, A.M., 2009. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 119, 1661. https://doi.org/10.1161/ circulationaha.108.821181. Gronthos, S., Franklin, D.M., Leddy, H.A., Robey, P.G., Storms, R.W., Gimble, J.M., 2001. Surface protein characterization of human adipose tissue‐derived stromal cells. J. Cell. Physiol. 189 (1), 54–63. https://doi.org/10.1002/jcp.1138. Haberka, M., Skilton, M., Biedroń, M., Szóstak-Janiak, K., Partyka, M., Matla, M., Gąsior, Z., 2019. Obesity, visceral adiposity and carotid atherosclerosis. J. Diabetes Complications. 33, 302–306. https://doi.org/10.1016/j.jdiacomp.2019.01.002. Hamblin, M., Chang, L., Zhang, H., Yang, K., Zhang, J., Chen, Y.E., 2010. Vascular smooth muscle cell peroxisome proliferator-activated receptor-γ deletion promotes abdominal aortic aneurysms. J. Vasc. Surg. 52, 984–993. https://doi.org/10.1016/j.jvs. 2010.05.089. Han, F., Li, K., Pan, R., Xu, W., Han, X., Hou, N., Sun, X., 2018. Calycosin directly improves perivascular adipose tissue dysfunction by upregulating the adiponectin/ AMPK/eNOS pathway in obese mice. Food Funct. 9, 2409–2415. https://doi.org/10. 1039/C8FO00328A. Han, F., Hou, N., Liu, Y., Huang, N., Pan, R., Zhang, X., Mao, E., Sun, X., 2019. Liraglutide improves vascular dysfunction by regulating a cAMP-independent PKA-AMPK pathway in perivascular adipose tissue in obese mice. Biomed. Pharmacother. 120,

12

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M. Queiroz and C.M. Sena

Mitchell, G.F., Parise, H., Benjamin, E.J., Larson, M.G., Keyes, M.J., Vita, J.A., Vasan, R.S., Levy, D., 2004. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension 43, 1239–1245. https://doi.org/10.1161/01.HYP.0000128420.01881.aa. Nacci, C., Leo, V., De Benedictis, L., Potenza, M.A., Sgarra, L., Maria, A., Quon, M.J., Montagnani, M., 2016. Infliximab therapy restores adiponectin expression in perivascular adipose tissue and improves endothelial nitric oxide-mediated vasodilation in mice with type 1 diabetes. Vascul. Pharmacol. 87, 83–91. https://doi.org/10. 1016/j.vph.2016.08.007. Navab, M., Ananthramaiah, G.M., Reddy, S.T., Van Lenten, B.J., Ansell, B.J., Fonarow, G.C., Vahabzadeh, K., Hama, S., Hough, G., Kamranpour, N., Berliner, J.A., Lusis, A.J., Fogelman, A.M., 2004. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J. Lipid Res. 45, 993–1007. https://10.1194/jlr. R400001-JLR200. Nichols, W., O’Rourke, M., Viachopoulos, C., 2011. McDonald’s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, 6th ed. CRC Press, New York. Nosalski, R., Guzik, T.J., 2017. Perivascular adipose tissue inflammation in vascular disease. Br. J. Pharmacol. 174, 3496–3513. https://doi.org/10.1111/bph.13705. Öhman, M.K., Luo, W., Wang, H., Guo, C., Abdallah, W., Russo, H.M., Eitzman, D.T., 2011. Perivascular visceral adipose tissue induces atherosclerosis in apolipoprotein E deficient mice. Atherosclerosis 219, 33–39. https://doi.org/10.1016/j. atherosclerosis.2011.07.012. Ohyama, K., Matsumoto, Y., Amamizu, H., Uzuka, H., Nishimiya, K., Morosawa, S., Hirano, M., Watabe, H., Funaki, Y., Miyata, S., Takahashi, J., Ito, K., Shimokawa, H., 2017. Association of coronary perivascular adipose tissue inflammation and drug eluting stent-induced coronary hyperconstricting responses in pigs: (18)F-fluorodeoxyglucose positron emission tomography imaging study. Arterioscler. Thromb. Vasc. Biol. 37, 1757–1764. https://doi.org/10.1161/ATVBAHA.117.309843. Oikonomou, E.K., Marwan, M., Desai, M.Y., Mancio, J., Alashi, A., Centeno, E.H., Thomas, S., Herdman, L., Kotanidis, C.P., Thomas, K.E., Griffin, B.P., 2018. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data. Lancet 392, 929–939. https://doi.org/10.1016/S0140-6736(18) 31114-0. Ouyang, A., Olver, T.D., Emter, C.A., Fleenor, B.S., 2019. Chronic exercise training prevents coronary artery stiffening in aortic-banded miniswine: role of perivascular adipose-derived advanced glycation end products. J. Appl. Physiol. 127, 816–827. https://doi.org/10.1152/japplphysiol.00146.2019. Padilla, J., Jenkins, N.T., Vieira-Potter, V.J., Laughlin, M.H., 2013. Divergent phenotype of rat thoracic and abdominal perivascular adipose tissues. Am. J. Physiol. 304, R543–R552. https://doi.org/10.1152/ajpregu.00567.2012. Pan, H., Reilly, M.P., 2019. A protective smooth muscle cell transition in atherosclerosis. Nat. Med. 25, 1194–1195. https://doi.org/10.1038/s41591-019-0541-0. Pan, X.X., Cao, J.M., Cai, F., Ruan, C.C., Wu, F., Gao, P.J., 2018. Loss of miR-146b-3p inhibits perivascular adipocyte browning with cold exposure during aging. Cardiovasc. Drugs Ther. 32, 511–518. https://doi.org/10.1007/s10557-018-6814-x. Pan, X.X., Ruan, C.C., Liu, X.Y., Kong, L.R., Ma, Y., Wu, Q.H., Li, H.Q., Sun, Y.J., Chen, A.Q., Zhao, Q., Wu, F., Wang, X.J., Wang, J.G., Zhu, D.L., Gao, P.J., 2019. Perivascular adipose tissue-derived stromal cells contribute to vascular remodeling during aging. Aging Cell 18, e12969. https://doi.org/10.1111/acel.12969. Piacentini, L., Werba, J.P., Bono, E., Saccu, C., Tremoli, E., Spirito, R., Colombo, G.I., 2019. Genome-wide expression profiling unveils autoimmune response signatures in the perivascular adipose tissue of abdominal aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 39, 237–249. https://doi.org/10.1161/ATVBAHA.118.311803. Police, S.B., Thatcher, S.E., Charnigo, R., Daugherty, A., Cassis, L.A., 2009. Obesity promotes inflammation in periaortic adipose tissue and angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler. Thromb. Vasc. Biol. 29, 1458–1464. https://doi.org/10.1161/ATVBAHA.109.192658. Quesada, I., Cejas, J., García, R., Cannizzo, B., Redondo, A., Castro, C., 2018. Vascular dysfunction elicited by a cross talk between periaortic adipose tissue and the vascular wall is reversed by pioglitazone. Cardiovasc. Ther. 36, e12322. https://doi.org/10. 1111/1755-5922.12322. Rademakers, T., Douma, K., Hackeng, T.M., Post, M.J., Sluimer, J.C., Daemen, M.J., Biessen, E.A., Heeneman, S., van Zandvoort, M.A., 2013. Plaque-associated vasa vasorum in aged apolipoprotein E-deficient mice exhibit proatherogenic functional features in vivo. Arterioscler. Thromb. Vasc. Biol. 33, 249–256. https://doi.org/10. 1161/ATVBAHA.112.300087. Rittig, K., Staib, K., Machann, J., Böttcher, M., Peter, A., Schick, F., Claussen, C., Stefan, N., Fritsche, A., Häring, H.U., Balletshofer, B., 2008. Perivascular fatty tissue at the brachial artery is linked to insulin resistance but not to local endothelial dysfunction. Diabetologia 51, 2093–2099. https://doi.org/10.1007/s00125-008-1128-3. Rodriguez-Menocal, L., Faridi, M.H., Martinez, L., Shehadeh, L.A., Duque, J.C., Wei, Y., Mesa, A., Pena, A., Gupta, V., Pham, S.M., Vazquez-Padron, R.I., 2014. Macrophagederived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling. Am. J. Physiol. 306, H641–H653. https://doi.org/ 10.1152/ajpheart.00641.2013. Safar, M.E., Levy, B.I., Struijker-Boudier, H., 2003. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 107 (286), 4–2869. https://doi.org/10.1161/01.CIR.0000069826.36125.B4. Sagan, A., Mrowiecki, W., Mikolajczyk, T.P., Urbanski, K., Siedlinski, M., Nosalski, R., Korbut, R., Guzik, T.J., 2012. Local inflammation is associated with aortic thrombus formation in abdominal aortic aneurysms. Relationship to clinical risk factors. Thromb. Haemost. 108, 812–823. https://doi.org/10.1160/TH12-05-0339. Sakaue, T., Suzuki, J., Hamaguchi, M., Suehiro, C., Tanino, A., Nagao, T., Uetani, T., Aono, J., Nakaoka, H., Kurata, M., Sakaue, T., 2017. Perivascular adipose tissue angiotensin II type 1 receptor promotes vascular inflammation and aneurysm

Lefranc, C., Friederich-Persson, M., Braud, L., Palacios-Ramirez, R., Karlsson, S., Boujardine, N., Motterlini, R., Jaisser, F., Nguyen Dinh Cat, A., 2019. MR (mineralocorticoid receptor) induces adipose tissue senescence and mitochondrial dysfunction leading to vascular dysfunction in obesity. Hypertension 73, 458–468. https://doi.org/10.1161/hypertensionaha.118.11873. Lehman, S.J., Massaro, J.M., Schlett, C.L., O’Donnell, C.J., Hoffmann, U., Fox, C.S., 2010. Peri-aortic fat, cardiovascular disease risk factors, and aortic calcification: the Framingham Heart Study. Atherosclerosis 210, 656–661. https://doi.org/10.1016/j. atherosclerosis.2010.01.007. Li, M.W., Mian, M.O., Barhoumi, T., Rehman, A., Mann, K., Paradis, P., Schiffrin, E.L., 2013. Endothelin-1 overexpression exacerbates atherosclerosis and induces aortic aneurysms in apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 33, 2306–2315. https://doi.org/10.1161/ATVBAHA.113.302028. Li, H., Wang, Y.P., Zhang, L.N., Tian, G., 2014. Perivascular adipose tissue-derived leptin promotes vascular smooth muscle cell phenotypic switching via p38 mitogen-activated protein kinase in metabolic syndrome rats. Exp. Biol. Med. 239, 954–965. https://doi.org/10.1177/1535370214527903. Li, C., Wang, Z., Wang, C., Ma, Q., Zhao, Y., 2015. Perivascular adipose tissue-derived adiponectin inhibits collar-induced carotid atherosclerosis by promoting macrophage autophagy. PLoS One 10, e0124031. https://doi.org/10.1371/journal.pone. 0124031. Libby, P., Ridker, P.M., Hansson, G.K., 2009. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol. 54, 2129–2138. https://doi.org/10. 1016/j.jacc.2009.09.009. Libby, P., Buring, J.E., Badimon, L., Hansson, G.K., Deanfield, J., Bittencourt, M.S., Tokgözoğlu, L., Lewis, E.F., 2019. Atherosclerosis. Nat. Rev. Dis. Primers 5, 56. https://doi.org/10.1038/s41572-019-0106-z. Lin, A., Nerlekar, N., Munnur, R.K., Kataoka, Y., Andrews, J., Dey, D., Nicholls, S.J., Wong, D.T., 2019. Cholesterol crystal-induced coronary inflammation: Insights from optical coherence tomography and pericoronary adipose tissue computed tomography attenuation. J. Cardiovasc. Comput. Tomogr. https://doi.org/10.1016/j.jcct. 2019.11.011. pii: S1934-5925(19)30352-1. Lumeng, C.N., Bodzin, J.L., Saltiel, A.R., 2007. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184. https://doi. org/10.1172/JCI29881. Lyle, A.N., Raaz, U., 2017. Killing me unsoftly causes and mechanisms of arterial stiffness. Arterioscler. Thromb. Vasc. Biol. 37, e1–e11. https://doi.org/10.1161/ATVBAHA. 116.308563. Mancia, G., Fagard, R., Narkiewicz, K., Redon, J., Zanchetti, A., Böhm, M., Christiaens, T., Cifkova, R., De Backer, G., Dominiczak, A., Galderisi, M., Grobbee, D.E., Jaarsma, T., Kirchhof, P., Kjeldsen, S.E., Laurent, S., Manolis, A.J., Nilsson, P.M., Ruilope, L.M., Schmieder, R.E., Sirnes, P.A., Sleight, P., Viigimaa, M., Waeber, B., Zannad, F., 2013. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood Press. 22, 193–278. https://doi.org/10.3109/08037051.2013.812549. Margaritis, M., Antonopoulos, A.S., Digby, J., Lee, R., Reilly, S., Coutinho, P., Shirodaria, C., Sayeed, R., Petrou, M., De Silva, R., Jalilzadeh, S., 2013. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation 127, 2209–2221. https://doi.org/10.1161/CIRCULATIONAHA.112.001133. Mattson, M.P., 2010. Perspective: does brown fat protect against diseases of aging? Ageing Res. Rev. 9, 69–76. https://doi.org/10.1016/j.arr.2009.11.004. Mattu, H.S., Randeva, H.S., 2013. Role of adipokines in cardiovascular. J. Endocrinol. 216, T17–T36. https://doi.org/10.1530/JOE-12-0232. Mazurek, T., Kobylecka, M., Zielenkiewicz, M., Kurek, A., Kochman, J., Filipiak, K.J., Mazurek, K., Huczek, Z., Królicki, L., Opolski, G., 2017. PET/CT evaluation of (18)FFDG uptake in pericoronary adipose tissue in patients with stable coronary artery disease: Independent predictor of atherosclerotic lesions’ formation? J. Nucl. Cardiol. 24, 1075–1084. https://doi.org/10.1007/s12350-015-0370-6. Meijer, R.I., Bakker, W., Alta, C.L.A., Sipkema, P., Yudkin, J.S., Viollet, B., Richter, E.A., Smulders, Y.M., van Hinsbergh, V.W., Serné, E.H., Eringa, E.C., 2013. Perivascular adipose tissue control of insulin-induced vasoreactivity in muscle is impaired in db/ db mice. Diabetes 62, 590–598. https://doi.org/10.2337/db11-1603. Meijer, R.I., Serné, E.H., Korkmaz, H.I., van der Peet, D.L., de Boer, M.P., Niessen, H.W., van Hinsbergh, V.W., Yudkin, J.S., Smulders, Y.M., Eringa, E.C., 2015. Insulin-induced changes in skeletal muscle microvascular perfusion are dependent upon perivascular adipose tissue in women. Diabetologia. 58, 1907–1915. https://doi.org/ 10.1007/s00125-015-3606-8. Meyer, M.R., Fredette, N.C., Daniel, C., Sharma, G., Amann, K., Arterburn, J.B., Barton, M., Prossnitz, E.R., 2016. Obligatory role for GPER in cardiovascular aging and disease. Sci. Signal. 9, ra105. https://doi.org/10.1126/scisignal.aag0240. Meziat, C., Boulghobra, D., Strock, E., Battault, S., Bornard, I., Walther, G., Reboul, C., 2019. Exercise training restores eNOS activation in the perivascular adipose tissue of obese rats: impact on vascular function. Nitric Oxide 86, 63–67. https://doi.org/10. 1016/j.niox.2019.02.009. Mikolajczyk, T.P., Nosalski, R., Skiba, D.S., Koziol, J., Mazur, M., Justo‐Junior, A.S., Kowalczyk, P., Kusmierczyk, Z., Schramm‐Luc, A., Luc, K., Maffia, P., 2019. 1,2,3,4, 6‐Penta‐O‐galloyl‐β‐d‐glucose modulates perivascular inflammation and prevents vascular dysfunction in angiotensin II‐induced hypertension. Br. J. Pharmacol. 176, 1951–1965. https://doi.org/10.1111/bph.14583. Min, S.Y., Kady, J., Nam, M., Rojas-Rodriguez, R., Berkenwald, A., Kim, J.H., Noh, H.L., Kim, J.K., Cooper, M.P., Fitzgibbons, T., Brehm, M.A., 2016. Human’brite/beige’adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat. Med. 22, 312–318. https://doi.org/10.1038/nm. 4031.

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M. Queiroz and C.M. Sena

Tanaka, H., Zaima, N., Sasaki, T., Sano, M., Yamamoto, N., Saito, T., Inuzuka, K., Hayasaka, T., Goto-Inoue, N., Sugiura, Y., Sato, K., 2015. Hypoperfusion of the adventitial vasa vasorum develops an abdominal aortic aneurysm. PLoS One 10, e0134386. https://doi.org/10.1371/journal.pone.0134386. Trouwborst, I., Bowser, S.M., Goossens, G.H., Blaak, E.E., 2018. Ectopic fat accumulation in distinct insulin resistant phenotypes; targets for personalized nutritional interventions. Front. Nutr. 5, 77. https://doi.org/10.3389/fnut.2018.00077. Usher, M.G., Duan, S.Z., Ivaschenko, C.Y., Frieler, R.A., Berger, S., Schütz, G., Lumeng, C.N., Mortensen, R.M., 2010. Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice. J. Clin. Invest. 120, 3350–3364. https://doi.org/10.1172/JCI41080. Vaitkevicius, P.V., Fleg, J.L., Engel, J.H., O’Connor, F.C., Wright, J.G., Lakatta, L.E., Yin, F.C., Lakatta, E.G., 1993. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation 88, 1456–1462. https://doi.org/10.1161/01.cir.88.4. 1456. van Marken Lichtenbelt, W.D., Vanhommerig, J.W., Smulders, N.M., Drossaerts, J.M., Kemerink, G.J., Bouvy, N.D., Schrauwen, P., Teule, G.J., 2009. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508. https://doi.org/10. 1056/NEJMoa0808718. van Sloten, T.T., Schram, M.T., van den Hurk, K., Dekker, J.M., Nijpels, G., Henry, R.M., Stehouwer, C.D., 2014. Local stiffness of the carotid and femoral artery is associated with incident cardiovascular events and all-cause mortality: the Hoorn study. J. Am. Coll. Cardiol. 63, 1739–1747. https://doi.org/10.1016/j.jacc.2013.12.041. Verhagen, S.N., Visseren, F.L., 2011. Perivascular adipose tissue as a cause of atherosclerosis. Atherosclerosis 214, 3–10. https://doi.org/10.1016/j.atherosclerosis.2010. 05.034. Villacorta, L., Chang, L., 2015. The role of perivascular adipose tissue in vasoconstriction, arterial stiffness, and aneurysm. Horm. Mol. Biol. Clin. Investig. 21, 137–147. https://doi.org/10.1515/hmbci-2014-0048. Villarroya, F., Cereijo, R., Villarroya, J., Giralt, M., 2017a. Brown adipose tissue as a secretory organ. Nat. Rev. Endocrinol. 13, 26–35. https://doi.org/10.1038/nrendo. 2016.136. Villarroya, F., Gavaldà-Navarro, A., Peyrou, M., Villarroya, J., Giralt, M., 2017b. The lives and times of brown adipokines. Trends Endocrinol. Metab. 28, 855–867. https://doi. org/10.1016/j.tem.2017.10.005. Wang, X., Pu, H., Ma, C., Jiang, T., Wei, Q., Zhang, C., Duan, M., Shou, X., Su, L., Zhang, J., Yang, Y., 2014. Adiponectin abates atherosclerosis by reducing oxidative stress. Med. Sci. Monit. 20, 1792–1800. https://doi.org/10.12659/MSM.892299. Withers, S.B., Bussey, C.E., Saxton, S.N., Melrose, H.M., Watkins, A.E., Heagerty, A.M., 2014. Mechanisms of adiponectin-associated perivascular function in vascular disease. Arterioscler. Thromb. Vasc. Biol. 34, 1637–1642. https://doi.org/10.1161/ ATVBAHA.114.303031. Witztum, J.L., Steinberg, D., 2001. The oxidative modification hypothesis of atherosclerosis: does it hold for humans? Trends Cardiovasc. Med. 11, 93–102. https://doi. org/10.1016/S1050-1738(01)00111-6. Wójcicka, G., Jamroz-Wiśniewska, A., Atanasova, P., Chaldakov, G.N., Chylińska-Kula, B., Bełtowski, J., 2011. Differential effects of statins on endogenous H2S formation in perivascular adipose tissue. Pharmacol. Res. 63, 68–76. https://doi.org/10.1016/j. phrs.2010.10.011. Xia, N., Li, H., 2017. The role of perivascular adipose tissue in obesity‐induced vascular dysfunction. Br. J. Pharmacol. 174, 3425–3442. Xia, N., Weisenburger, S., Koch, E., Burkart, M., Reifenberg, G., Förstermann, U., Li, H., 2017. Restoration of perivascular adipose tissue function in diet‐induced obese mice without changing bodyweight. Br. J. Pharmacol. 174, 3443–3453. https://doi.org/ 10.1111/bph.13703. Xiong, W., Zhao, X., Garcia-Barrio, M.T., Zhang, J., Lin, J., Chen, Y.E., Jiang, Z., Chang, L., 2017. MitoNEET in perivascular adipose tissue blunts atherosclerosis under mild cold condition in mice. Front. Physiol. 8, 1032. https://doi.org/10.3389/fphys.2017. 01032. Xu, X., Wang, B., Ren, C., Hu, J., Greenberg, D.A., Chen, T., Xie, L., Jin, K., 2017. Agerelated impairment of vascular structure and functions. Aging Dis. 8, 590–610. https://doi.org/10.14336/AD.2017.0430. Yang, F.S., Yun, C.H., Wu, T.H., Hsieh, Y.C., Bezerra, H.G., Liu, C.C., Wu, Y.J., Kuo, J.Y., Hung, C.L., Hou, C.J.Y., Yeh, H.I., 2013. High pericardial and peri-aortic adipose tissue burden in pre-diabetic and diabetic subjects. BMC Cardiovasc. Disord. 13, 98. https://doi.org/10.1186/1471-2261-13-98. Ye, M., Ruan, C.C., Fu, M., Xu, L., Chen, D., Zhu, M., Zhu, D., Gao, P., 2019. Developmental and functional characteristics of the thoracic aorta perivascular adipocyte. Cell. Mol. Life Sci. 76, 777–789. https://doi.org/10.1007/s000180182970-1. Zhang, Z.B., Ruan, C.C., Lin, J.R., Xu, L., Chen, X.H., Du, Y.N., Fu, M.X., Kong, L.R., Zhu, D.L., Gao, P.J., 2018. Perivascular adipose tissue–derived PDGF-D contributes to aortic aneurysm formation during obesity. Diabetes 67, 1549–1560. https://doi.org/ 10.2337/db18-0098. Zou, L., Wang, W., Liu, S., Zhao, X., Lyv, Y., Du, C., Su, X., Geng, B., Xu, G., 2016. Spontaneous hypertension occurs with adipose tissue dysfunction in perilipin-1 null mice. Biochim. Biophys. Acta 1862, 182–191. https://doi.org/10.1016/j.bbadis. 2015.10.024. Zuk, P.A., Zhu, M., Ashjian, P., De Ugarte, D.A., Huang, J.I., Mizuno, H., Alfonso, Z.C., Fraser, J.K., Benhaim, P., Hedrick, M.H., 2002. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell 13 (12), 4279–4295. https://doi.org/10.1091/ mbc.e02-02-0105.

formation. Hypertension 70, 780–789. https://doi.org/10.1161/ HYPERTENSIONAHA.117.09512. Salim, H.M., Fukuda, D., Higashikuni, Y., Tanaka, K., Hirata, Y., Yagi, S., Soeki, T., Shimabukuro, M., Sata, M., 2017. Teneligliptin, a dipeptidyl peptidase-4 inhibitor, attenuated pro-inflammatory phenotype of perivascular adipose tissue and inhibited atherogenesis in normoglycemic apolipoprotein-E-deficient mice. Vascul. Pharmacol. 96, 19–25. https://doi.org/10.1016/j.vph.2017.03.003. Sanchez-Gurmaches, J., Guertin, D.A., 2014. Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat. Commun. 5, 4099. https:// doi.org/10.1038/ncomms5099. Sanna, F., Margaritis, M., Antoniades, C., 2017. Perivascular adipose tissue as an endocrine organ: the role of statins. Curr. Pharm. Des. 26. https://doi.org/10.2174/ 1381612823666170926133843. Saxton, S.N., Ryding, K.E., Aldous, R.G., Withers, S.B., Ohanian, J., Heagerty, A.M., 2018. Role of sympathetic nerves and adipocyte catecholamine uptake in the vasorelaxant function of perivascular adipose tissue. Arterioscler. Thromb. Vasc. Biol. 38, 880–891. https://doi.org/10.1161/ATVBAHA.118.310777. Saxton, S.N., Clark, B.J., Withers, S.B., Eringa, E.C., Heagerty, A.M., 2019. Mechanistic links between obesity, diabetes, and blood pressure: role of perivascular adipose tissue. Physiol. Rev. 99, 1701–1763. https://doi.org/10.1152/physrev.00034.2018. Sena, C.M., Matafome, P., Louro, T., Nunes, E., Fernandes, R., Seiça, R.M., 2011. Metformin restores endothelial function in aorta of diabetic rats. Br. J. Pharmacol. 163, 424–437. https://doi.org/10.1111/j.1476-5381.2011.01230.x. Sena, C.M., Pereira, A., Fernandes, R., Letra, L., Seiça, R.M., 2017. Adiponectin improves endothelial function in mesenteric arteries of rats fed a high‐fat diet: role of perivascular adipose tissue. Br. J. Pharmacol. 174, 3514–3526. https://doi.org/10.1111/ bph.13756. Shields, K.J., Stolz, D., Watkins, S.C., Ahearn, J.M., 2011. Complement proteins C3 and C4 bind to collagen and elastin in the vascular wall: a potential role in vascular stiffness and atherosclerosis. Clin. Transl. Sci. 4, 146–152. https://doi.org/10.1111/j. 1752-8062.2011.00304.x. Shimizu, K., Mitchell, R.N., Libby, P., 2006. Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 26, 987–994. https://doi.org/10.1161/01.ATV.0000214999.12921.4f. Shore, A., Karamitri, A., Kemp, P., Speakman, J.R., Lomax, M.A., 2010. Role of Ucp1 enhancer methylation and chromatin remodelling in the control of Ucp1 expression in murine adipose tissue. Diabetologia 53, 1164–1173. https://doi.org/10.1007/ s00125-010-1701-4. Silva, K.R., Côrtes, I., Liechocki, S., Carneiro, J.R.I., Souza, A.A.P., Borojevic, R., MayaMonteiro, C.M., Baptista, L.S., 2017. Characterization of stromal vascular fraction and adipose stem cells from subcutaneous, preperitoneal and visceral morbidly obese human adipose tissue depots. PLoS One 12 (3), e0174115. https://doi.org/10.1371/ journal.pone.0174115. Simperova, A., Al-Nakkash, L., Faust, J.J., Sweazea, K.L., 2016. Genistein supplementation prevents weight gain but promotes oxidative stress and inflammation in the vasculature of female obese ob/ob mice. Nutr. Res. 36, 789–797. https://doi.org/10. 1016/j.nutres.2016.03.011. Skiba, D.S., Nosalski, R., Mikolajczyk, T.P., Siedlinski, M., Rios, F.J., Montezano, A.C., Jawien, J., Olszanecki, R., Korbut, R., Czesnikiewicz‐Guzik, M., Touyz, R.M., 2017. Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis. Br. J. Pharmacol. 174, 4055–4069. https://doi.org/10.1111/bph.13685. Soltis, E.E., Cassis, L.A., 1991. Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clin. Exp. Hypertens. A. 13, 277–296. https://doi. org/10.3109/10641969109042063. Sousa, A.S., Sponton, A.C.D.S., Trifone, C.B., Delbin, M.A., 2019. Aerobic exercise training prevents perivascular adipose tissue (PVAT)-induced endothelial dysfunction in thoracic aorta of obese mice. Front. Physiol. 10, 1009. https://doi.org/10.3389/ fphys.2019.01009. Srikakulapu, P., Upadhye, A., Rosenfeld, S.M., Marshall, M.A., McSkimming, C., Hickman, A.W., Mauldin, I.S., Ailawadi, G., Lopes, M.B.S., Taylor, A.M., McNamara, C.A., 2017. Perivascular adipose tissue harbors atheroprotective IgM-producing B cells. Front. Physiol. 8, 719. https://doi.org/10.3389/fphys.2017.00719. Stenmark, K.R., Yeager, M.E., El Kasmi, K.C., Nozik-Grayck, E., Gerasimovskaya, E.V., Li, M., Riddle, S.R., Frid, M.G., 2013. The adventitia: essential regulator of vascular wall structure and function. Annu. Rev. Physiol. 75, 23–47. https://doi.org/10.1146/ annurev-physiol-030212-183802. Sun, Y., Li, J., Xiao, N., Wang, M., Kou, J., Qi, L., Huang, F., Liu, B., Liu, K., 2014. Pharmacological activation of AMPK ameliorates perivascular adipose/endothelial dysfunction in a manner interdependent on AMPK and SIRT1. Pharmacol. Res. 89, 19–28. https://doi.org/10.1016/j.phrs.2014.07.006. Szasz, T., Webb, R.C., 2012. Perivascular adipose tissue: more than just structural support. Clin. Sci. 122, 1–12. https://doi.org/10.1042/CS20110151. Szasz, T., Bomfim, G.F., Webb, R.C., 2013. The influence of perivascular adipose tissue on vascular homeostasis. Vasc. Health Risk Manag. 9, 105–116. https://doi.org/10. 2147/VHRM.S33760. Tabas, I., García-Cardeña, G., Owens, G.K., 2015. Recent insights into the cellular biology of atherosclerosis. J. Cell Biol. 209, 13–22. https://doi.org/10.1083/jcb.201412052. Takaoka, M., Suzuki, H., Shioda, S., Sekikawa, K., Saito, Y., Nagai, R., Sata, M., 2010. Endovascular injury induces rapid phenotypic changes in perivascular adipose tissue. Arterioscler. Thromb. Vasc. Biol. 30, 1576–1582. https://doi.org/10.1161/ ATVBAHA.110.207175.

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