Microvascular pericytes in brain-associated vascular disease

Biomedicine & Pharmacotherapy 121 (2020) 109633

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Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha

Review

Microvascular pericytes in brain-associated vascular disease a

a

Qi Liu , Yingxi Yang , Xiaonong Fan

b,c,

T

*

a

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, 314 An Shan Xi Road, Nan Kai District, Tianjin 300193, China Institute of acupuncture and moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, 314 An Shan Xi Road, Nan Kai District, Tianjin 300193, China c Tianjin Key Laboratory of Acupuncture and Moxibustion Science, National Acupuncture Clinical Research Center, China b

A R T I C LE I N FO

A B S T R A C T

Keywords: Pericytes Function Therapy Brain-associated vascular disease

Pericytes, as mural cells of microvessels, are important regulators of vascular structure formation and function maintenance in the process of cerebrovascular maturation, cerebrovascular homeostasis and disease. In the recent years, they have gradually become the hot spot of the research. In fact, pericytes are not isolated cells. Their functions can’t be played without the cooperation with surrounding cells. In the neurovascular unit (NVU), they communicate with other cells by direct contact or through signaling pathways to regulate cerebral vascular function and the state of blood vessels in response to changes in neural activity. Pericytes are closely related to the cerebrovascular and central nervous system disease. Currently, a large number of clinical and animal studies have confirmed that pericytes biological function is related to cerebral blood flow, blood-brain barrier permeability, cerebral vascular formation maintenance, and neuroinflammation. The objective of this review is to highlight the role of pericytes in cerebral microvessels as well as their relationships with stroke, dementia, and brain tumor disease. The possible pathogenic mechanisms between pericytes and these diseases will also be described. As a matter of fact, the role of pericytes in the brain-associated vascular disease may provide new ideas for clinical treatment.

1. Introduction Pericytes are multipotent cells that are present in every vascularized tissue of the body. The brain is a vascularized organ and the density of pericytes is the highest in brain. Therefore the role of pericytes in cerebral vessels can’t be ignored. With the development of research, the study of the blood vessel in cerebrovascular disease has expanded from unique consideration of endothelial cells to more attention on intimate anatomical and chemical relationship between neurons, astrocytes, pericytes, and extracellular matrix. With the advent of electron microscope, mature pericytes are now defined as multipotent cells embedded within the vascular basement membrane (BM) [1,2]. As a matter of fact, they are an important part of the basement membrane of blood microvessels. Pericytes are present at intervals along the walls of capillaries and postcapillary venules, and are surrounded by basement membrane [3]. Pericytes were first found and characterized by Eberth and Rouge in the 1870s, and Zimmermann named them until 1923 [2,4]. Besides, Zimmermann proposed three subtypes of pericytes along the vascular tree, which were based on their morphology, location within the vascular network, and function of these cells. Despite

pericytes have been discovered and studied a century ago, the unambiguous identification of them is still a problem due to cellular heterogeneity and unclear molecular markers. Consequently, the further exploration of them is affected to some extent. Pericytes are unique cells with the characteristics of macrophages and smooth muscle. Recently, more and more studies have begun to pay attention to the immunomodulatory activity of pericytes and have confirmed their stem cell properties. The biology of brain microvascular pericytes is critical for regulating various aspects of cerebrovascular function, including blood-brain barrier permeability, cerebral blood flow, vessel stability, angiogenesis and immune cell trafficking [5,6]. Most of previous functional studies have demonstrated that pericytes play key regulatory roles in cerebrovascular diseases. In fact, pericytes loss or dysfunction is involved in the pathogenesis of ischemic stroke, Alzheimer’s disease, vascular dementia and brain tumor. The functional summary of cerebral microvascular pericytes and its possible relationship with corresponding brain-associated vascular disease are the areas that are discussed deeply in this work.

⁎ Corresponding author at: Institute of acupuncture and moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, 314 An Shan Xi Road, Nan Kai District, Tianjin 300193, China. E-mail address: [email protected] (X. Fan).

https://doi.org/10.1016/j.biopha.2019.109633 Received 26 September 2019; Received in revised form 31 October 2019; Accepted 1 November 2019 0753-3322/ © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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Table 1 Pericyte Markers. Marker

Tissue/organ

Comments

References

PDGFR-β

Brain Retina Kidney Brain Retina Skeletal muscle Kidney Heart Brain Retin Skeletal muscle Kidney Heart Brain Kidney

receptor with tyrosin kinase activity; involved in pericytes proliferation and recruitment during angiogenesis;

[7,8,9]

membrane chondroitin sulfate proteoglycan; involved in pericyte recruitment to tumor vasculature

[7,8,9,10]

structural proteins； important for pericyte contraction and regulation of blood pressure; expression was not evident in the CNS under normal circumstances; expression in pericytes is commonly upregulated in tumors and in inflammation

[7,8,9,10,11]

structural protein; important for pericyte contraction and regulation of blood pressure; useful pericyte marker outside skeletal muscle and heart a GTP ase activating protein; up-regulated in pericytes during the early phases of physiologic and pathologic neovascularization; angiogenic pericyte marker type II membrane zincdependent metalloprotease; expressed mainly on brain pericytes; useful marker for brain pericytes gap junction protein; as a coreceptor of PDGF receptor-β to mediate pericyte recruitment to cerebrovascular endothelial cells

[7,8]

NG2

α-SMA

Desmin

RGS5

Brain Kidney

CD13

Brain

CD146

Brain Kidney

[8,12]

[7,13]

[7,8,14]

2. Identification of pericytes

3. Pericytes in neurovascular unit

Currently, there is a lot of controversy about the molecular markers of pericytes, the heterogeneous morphology and the marker expression of pericyte. Therefore, it’s a scientific challenge to identify them clearly. In the previous studies, the single marker of pericytes have led to deviation and misunderstanding of some of the results of the study. However, it has been shown that pericytes don’t have a unique marker that is completely known and these markers can also be expressed in other cells. Nonetheless, universal pericyte-positive markers have not yet been identified in different tissues and organs. Due to the heterogeneity of pericytes, multiple markers are usually used for their identification. Presently, the following pericytes markers have been widely studied, such as PDGFR-β, NG2, Desmin, α-SMA, RGS5, CD13, CD146, etc.(Table. 1) In fact, these markers are dynamic in expression and vary between organs, in different stages of development and in their pathophysiological responses.

Pericytes are important cells within the neurovascular unit (NVU) (Fig. 1) [15]. All the components of NVU (brain microvessel endothelial cells, pericytes, perivascular astrocytes, neuronal cells, etc.) must interact with each other and work in concert in order to maintain the normal physiological functions of the brain. NVU connects the vascular system with the neurons. It can tightly regulate the cerebral vascular function through the vascular system according to the neuronal response, which will consequently affect the state of blood vessels and blood flow in the brain [16,17]. In the previous studies, because pericytes were usually included in the blood-brain barrier(BBB), their role in the environmental balance within NVU was somehow neglected. Nevertheless, as a member of the NVU, pericytes of brain capillaries are positioned in the center of the NVU. Their unique position allows them to play a major role in regulating the function of the NVU. Related studies have found that the destruction of the NVU is related to substances released by the pericytes during inflammation. Matrix metalloproteinase-3 (MMP-3) from pericytes has an independent effect on neurovascular unit injury through Fig. 1. Neurovascular Units (capillary cross-section) schematic representation: Endothelial cell surrounding a blood vessel ensheathed by the basement membrane, pericytes and astrocyte-endfeet processes, which form the blood-brain barrier (BBB). Pericytes play an important role in maintaining the NVU physiological functions through close connection and interaction with other cells; close to the vessel, a microglial cell and a neuron are seen.

2

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affects the transport of nutrients to tissues even when the total blood flow is constant [33].

tight junction and laminin degradation [18]. More recently, it has been suggested that besides the crucial role of pericytes in maintaining the NVU, they also have stem cell-like properties and activities [19]. It has been shown that under ischemic/hypoxic conditions, pericytes can acquire multipotential stem cell activity and can differentiate into major components of the BBB/neurovascular unit [20]. Furthermore, many studies have demonstrated that vascular pericytes acquire multipotent vascular stem cells activity under pathological conditions and may become a novel source of microglia [21].

4.2. Pericytes regulate blood-brain barrier BBB is a multi-component system with very complex molecules and structures. The interaction between different components is critical to the formation and maturation of the barrier, both in the course of development and thereafter [34,35]. Pericytes are recognized as key players in barrier genesis and vessel stabilization [30,36]. Nakagawa et al. used the triple co-culture BBB model for the first time, consisting of pericytes, endothelial cells and astrocytes. They have found that pericytes of brain microvessel are able to enhance the BBB function of endothelial cells just like astrocytes [37]. Similarly, as BBB's three-dimensional in vitro model shows, pericytes and astrocytes appear to have different unique roles in BBB [38]. Even under the condition of cocultivation, pericytes have a higher resistance and low permeability when compared to astrocytes [37]. In platelet-derived growth factor-B (PDGF-B) or PDGF receptor beta (PDGFRβ) gene-knockout mice, the lack of pericytes leads to impaired endothelial differentiation, endothelial hyperplasia, and increases vascular leakage [39]. Underly et al. imaged pericyte-labeled transgenic mice with in vivo two-photon microscopy. These authors have found that pericytes contribute to rapid and localized proteolytic degradation of the BBB during cerebral ischemia through a rapid activation of matrix metalloproteinase-9 (MMP-9) [40]. Pericytes affect the BBB both by the direct and indirect way. Firstly, pericytes regulate the BBB at the level of endothelial junctions [41,42]. They may control endothelial function and differentiation through direct physical cell–cell contact in specialized junctions. Consequently, the endothelial cells of the BBB have extraordinarily high requirements for pericytes. The tight binding between pericytes and endothelial cells, through gap junction, peg-and-socket and adhesion plaques, makes pericytes the key cells for the maintenance and stabilization of BBB and development of BBB tight junctions (TJs) [15,37]. Endothelial cells are not the only cells that express TJ molecules. Pericytes control endothelial BBB tight and adhesion-associated protein expression as well as the arrangement of tight junction proteins [36,43]. They have been found to express a variety of TJ molecules including claudin-12, JAM, ZO-1, ZO-2 and occludin [44]. Among these TJ proteins, occludin and ZO-1 are important components of TJs and their expression level plays a critical role in regulating permeability changes at the tight junctions [45]. Hori et al. in vitro BBB model studies revealed that the pericytederived multimeric angiopoietin-1/Tie-2 pathway induces occludin expression [46]. Besides, Dohgu et al. found that pericytes participate in the intercellular junction and promote the P-pg function of brain endothelial cells through cell-to-cell contact and the production of soluble factors such as transforming growth factor-β (TGF-β) [47]. Expression of factor-β signal in pericytes initiates the production of extracellular matrix (ECM) molecules whereas TGF-β signaling in endothelial cells promotes the adhesion by up-regulating N-cadherin [48,49]. Furthermore, pericytes also directly express several barrier related transporters like ABCG2, P-gp, MRP 1, and GLUT-1 [44]. These transporters on pericytes might cooperate with those on endothelial cells to maintain the steady state of the peripheral nerves and the BBB. In addition, the regulation of BBB by pericytes is also manifested in other aspects. In pathological condition, pericytes participate in the recruitment of neutrophils into the sub-endothelial layer by secreting chemotactic agents IL8, metalloprotease MMP-2 and MMP-9, thus causes the destruction of the vascular wall as well as the contact between endothelial cells and cells [50,51]. Furthermore, proper investment of the cerebrovascular by astroglial end-feet is also mediated by pericytes, which may guide astrocytic foot processes to the endothelial tube and initiates proper end-foot polarization [34,52]. Armulik reported that pericytes induce polarization of astroglial end-feet around vessels and in disease pericytes degeneration leads to increased vessel

4. The function of pericytes 4.1. Pericytes in cerebral blood flow In the early 1870s, Eberth and Rouget ascribed contractile and blood flow regulation properties to pericytes [4]. In fact, pericytes might be contractile cells that are involved in regulation of capillary blood flow because of their the special perivascular location and their morphology [22]. The most recent research has increasingly demonstrated that pericytes, similar to vascular smooth muscle cells (VSMCs), contain contractile filaments composed of vimentin and alpha-smooth muscle actin (α-SMA), which are capable of regulating vasomotion especially in capillaries [23,24]. Besides, recent studies in the retina have suggested the presence of gap junction communication between neighboring pericytes involved in conductive vasomotor constrictions [25]. Related retinal studies have also found that pericytes contract following the increase of ATP. The raise of ATP induces depolarizing changes in the ionic currents, which increases calcium levels and finally leads to the contraction of pericytes [26]. Moreover, it has been well established that brain pericytes have contractile effects not only in culture, but also in isolated organ preparations [27,28]. Whether pericytes can regulate cerebral blood flow has always been a controversial issue. Commonly, blood flow is considered as being regulated by the anterior arteriole of capillaries rather than capillaries. However, related research have found that most of the noradrenergic innervations of CNS blood vessels (65%) is of the capillaries rather than arterioles [27]. In point of fact, interactions between squeezed red blood cells and the vessel wall govern the rheology in capillaries, so that small diameter changes are likely to have a large impact on blood flow [29]. Recently, Hall et al. reported a faster onset of capillary dilation in vivo when compared to arteriole dilation, much of the increase in blood flow is generated by dilation of capillaries following the relaxation of contractile pericytes [27,30]. Accordingly, pericytes are thought to have the function of controlling cerebral blood flow physiologically, and play a key role in regulating cerebral blood flow in microvessels by contracting and relaxing. On their side, Fernandez-Klett et al. used two-photon microscopy to study in real time pericytes and the dynamic changes of capillary diameter and blood flow in the cortex of anesthetized mice. Their results provide in vivo evidence that pericytes can modulate capillary blood flow in the brain under pathological conditions [28]. Kisler et al. using loss-of-function pericyte-deficient mice, showed that pericytes degeneration diminishes the cerebral blood flow response of the global and individual capillary to neuronal stimulus, which results in neurovascular uncoupling [31]. Additionally, Tachibana et al. injected C3H/ 10T1/2 cell derived pericytes into the cortex of APP/PS1 mice, and found that microcirculation in the specific region of pericyte-implanted hemisphere was considerably increased compared to that of the contralateral hemisphere. This proves that the implantation of pericytes into the brain can increase cerebral blood flow [32]. Furthermore, Yemisci et al. demonstrated, in a mouse brain ischemia–reperfusion model, that ischemia induces a sustained contraction of pericytes on the capillary of the intact mouse brain and continues to affect cerebral blood flow even after the reflow of the occluded artery [23]. In addition to changing the total blood flow, the contraction and relaxation of pericytes also alters the capillary transit time heterogeneity, which 3

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critical role in vascular basement membrane formation and endothelial cell tube maturation in catalyzed events [70].

permeability [52]. 4.3. Pericytes in angiogenesis and maintenance

4.4. Pericytes regulate neuroinflammation In the process of angiogenesis, endothelial cells form the inner lining of the vessel wall and provide a noncoagulant surface for blood. Perivascular cells (pericytes or vascular smooth muscle cells)envelop the surface of the vascular tube [53] to increase their stability and regulate their perfusion. Previous studies on blood vessels have focused mainly on the composition of endothelial cells while putting less emphasis on the eventual role of pericytes. In fact, pericytes also play an active role in cerebral vascular formation and stability. Overall, the process of angiogenesis is the interaction between endothelial cells and pericytes. They jointly regulate vessel formation, maturation, and specification with the coordination of many strictly regulated molecules. Pericytes are involved in the whole angiogenic process, including sprout formation and migration, maturation of new vessels, and termination of angiogenesis [19]. These processes are related to the signal molecular of pericytes action. Research have supported that a number of signal molecules associated with pericytes act as important regulators for cerebrovascular formation and maintenance, each of which is regulated in different processes and at different developmental stages. Presently, several signal molecules have been extensively studied in regard of angiogenesis. As the principal drivers of angiogenesis [54], it was demonstrated that vascular endothelial growth factors (VEGF) can initiate blood vessel formation and activate a chain of molecular and cellular events [55]; the angiopoietin–Tie and the platelet-derived growth factor (PDGF/PDGFR) control the late steps of angiogenesis including vessel maturation and vascular remodeling [56]. Pericytes are associated with the above multiple signaling molecules and participate in the regulation of multiple signaling pathways. VEGF and its receptor pathway trigger the early events of angiogenesis and invasive capillary formation, which is absolutely essential for vasculogenesis and angiogenesis [57,58]. Eilken et al. in their study of postnatal retinal vasculature, proved that pericytes are capable of guiding sprouting processes by migrating ahead of endothelial cells and expressing VEGF receptor 1 [59]. Besides, Bai et al. demonstrated the role of pericyte-derived VEGF in stroke, human brain pericytes treated with sodium cyanide and glucose deprivation can increase the expression of VEGF by activating tyrosine kinase Src [60]. PDGF-B is a crucial player in recruiting pericytes into newly formed blood vessels [61]. Abramsson et al. showed that C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment. This leads to pericyte detachment and delayed pericyte migration in vivo and produces defective investment of pericytes in the microvascular system [62]. Moreover, through the study of PDGF-B deficient mice, it was found that endothelial cells of PDGF-B deficient mice are unable to attract PDGFR-β-positive progenitors of pericytes, which eventually leads to instability and degeneration of blood vessels [63]. Angiopoietins are also important for vascular development and stabilization as they are considered to be necessary for the stability of mature vessels [64]. Indeed, Angiopoietin-1/Tie2 receptor is involved in the secondary stages of blood vessel formation [65]. Park et al. proved for the first time that hypoxia upregulates Ang1 expression via HIF2α-mediated transcriptional activation in pericytes, which plays a key role in angiogenesis [66]. It is well known that the termination of mature blood vessels is the formation of the basal lamina. Previous studies have shown that the regulation of basal lamina level is indispensable for vascular adaptability to an ever-changing environment [67]. Pericytes can synthesize static substances and components of the ECM of blood vessels, such as proteoglycans, collagen and elastin [19,68,69]. Accordingly, in some cases pericytes can be directly associated with the changes of the basal lamina. More recently, Stratman et al. have found that endothelial cellpericyte heterotypic cell-cell interactions control basement membrane matrix assembly. They have also demonstrated that pericytes play a

Neuroinflammation is the response of multiple cells in the neurovascular unit(NVU) that is related to the blood-brain barrier(BBB) [71]. Indeed, due to the existence of BBB, blood vessels are another important site of cerebral inflammation [72]. As mentioned above, pericytes have a unique position in the NVU and provide support to BBB maintenance. They can serve as an important integrator, coordinator and effector of many neurovascular functions. This localization puts pericytes in a pivotal position for the regulation of neuroinflammation. More recently, there has been an acknowledgment about the possible involvement of pericytes in neuroinflammation. A three-dimensional model of human blood-brain barrier constructed in microfluidic chips has demonstrated that pericytes differ from endothelial cells and astrocytes. In fact, they independently contribute to the inflammation stimuli [73]. Additionally, the potential dysfunction of pericytes during inflammation-stimulated states results in diminished barrier support [74]. The loss of this barrier drastically enhances vascular permeability and has an internal relationship with peripheral immune cells or inflammatory substances entering the brain parenchyma. Recently, it has been shown that brain pericytes have many properties of immune regulating cells and may play a unique role in immune infiltration [75–77]. The immune activation of brain pericytes may contribute to the transmission of inflammatory signals within the interior of brain. The immune infiltration function of pericytes is manifested in many aspects. Firstly, pericytes are active participants in leukocyte migration across barriers in different organs [78,79]. Pericytes enhance leukocyte exosmosis and recruitment by expressing a variety of mediators and promote neuroinflammation [76]. In regards to human brain pericytes, chemokines represent the predominant component of their secretome. Under the condition of inflammatory stimulation, pericytes recruit white blood cells and related cells to gather at the inflamed site by secreting large amounts of chemokines. Thereafter, they attract circulating white blood cells into the brain through concentration gradient [50,75,80,81]. In addition, pericytes also express a variety of adhesion molecules to guide leukocyte migration and crawling. Lipopolysaccharide (LPS) induces nuclear translocation of the transcription factor NF-kB in stimulated pericytes. This promotes the over expression of adhesion molecules, the up-regulation of the intercellular adhesion molecule-1(ICAM-1) and vascular cell adhesion molecule-1(VCAM-1), which results in an increased adhesion of leukocytes to an pericyte monolayer [80]. Proebstl et al. through direct analysis of leukocyte–pericyte interactions in inflamed tissues using confocal intravital microscopy, have found that pericytes express ICAM-1 and VCAM-1, which can promote neutrophil adhesion and help them crawl along pericyte processes to gaps between adjacent pericytes [51]. Furthermore, Stark et al. have found in their in vivo studies that pericytes in response to inflammatory mediators can up-regulate the expression of the adhesion molecule ICAM-1 and release the chemoattractant MIF to subsequently attract innate leukocytes and ‘instruct’ them with patternrecognition and motility programs [82]. Another aspect of the immune infiltration function of pericytes is its response and expression to a large number of inflammatory molecules. Kovac et al. by studying the immunological profile of brain pericytes in the quiescent and immune-challenged state, have found that LPS stimulates cytokine release by primary mouse brain pericytes; pericytes can significantly release IL-1a, TNF-a, IL-3, IL-9, IL-13 and other proinflammatory cytokines [75]. Persidsky et al. in the study of genes regulating inflammation, have found that 48 and 38 out of 84 pro-inflammatory genes are upregulated more than twofold in TNF-a or IL-1β treated pericytes, respectively [74]. Furthermore, pericytes meditate the propagation of peripheral or CNS inflammation [76]. They can propagate inflammatory responses generated elsewhere, including 4

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circulating proinflammatory cytokines and compromised cells present in peripheral sterile inflammation or bacterial or viral infection to enhance vascular inflammation [76].

injury. Accordingly, Birbrair et al. have found its of type 1 (rather than type 2) pericytes that increase and accumulate near the fibrotic tissue while producing collagen in an organ-dependent manner [95].

5. Pericytes and brain-associated vascular disease

5.2. Dementia

5.1. Stroke

Antecedently, Alzheimer's disease (AD) had become synonymous with dementia and its pathological mechanism mainly focused on the amyloid/tau hypothesis [96]. Interestingly, a recent study have found that vascular disorder is an early pathological event during Alzheimer's disease development, which precedes other pathological changes such as Aβ deposition, metabolic dysfunction, functional impairment and structural atrophy [97]. Also, other studies have proved that age-dependent vascular injury precedes neuronal degenerative changes, learning and memory impairment and neuroinflammatory responses in pericyte deficient mice [43]. The brain is a highly vascularized organ. In fact, vascular contributions to cognitive impairment and dementia of later life are common, whether it's vascular cognitive impairment (VCI) or AD [98]. As the key cells of microcirculation, there have been a large number of studies confirming the relationship of pericytes with cognitive impairment. Firstly, from an epidemiological standpoint, studies have shown vascular risk factors increase risk of both AD and VCI, especially hypertension and diabetes [99,100]. Relevant studies have confirmed that risk factors (hypertension, diabetes, etc.) related to cognitive impairment are associated with pericytes and may lead to pericytes apoptosis and dropout [101]. Secondly, epidemiology aside, there is a strong pathologic relationship between cerebrovascular disease and cognitive impairment, including the destruction of blood-brain barrier, cerebral perfusion disorder and neurovascular coupling damage [102,103]. Among these events, the function of cerebral microvessels can't be ignored [104]. In pericyte-deficient mice, blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leads to secondary neuronal degenerative changes [43]. Furthermore, a recent study using the rat model of cerebral small vessel disease, has shown that intravenous infusion of mesenchymal stem cells (MSCs) can promote the proliferation and differentiation of endothelial cells and pericytes, the remodeling of impaired microvasculature and the restoration of the transvascular BBB transport system. Accordingly, this improves Aβ clearance and inhibits Aβ accumulation, thus inhibiting brain atrophy and ameliorating cognitive function [105]. As mentioned earlier, pericytes are located in neurovascular units and play an important role in neurovascular coupling. Using a loss-offunction pericyte-deficient mice, Kisler et al. have found that pericyte degeneration results in neurovascular uncoupling and reduces oxygen supply to brain and metabolic stress [31]. In addition, the vascular damage caused by pericyte loss can cause neurodegeneration. Pericyte loss accelerates amyloid angiopathy and cerebral β-amyloidosis by diminishing the clearance of soluble Aβ40 and Abβ42 from brain interstitial fluid, even without the accumulation of Aβ [106]. Similarly, Miners et al. clinical studies have found that the loss of PDGFRB within the precuneus in AD is related to fibrillar Aβ accumulation, also associated with fibrinogen leakage and reduced oxygenation [107]. Consistently, Tachibana et al. implantation of mesenchymal stem cell–derived pericytes into amyloid model mice, demonstrated that pericyte implantation reduces Aβ deposition in the hippocampus and that cerebral microcirculations are significantly increased compared to those before implantation [32]. Furthermore, pericytes control white matter structure and function. Using pericyte-deficient mice, Montagne et al. showed that pericyte degeneration disrupts the white matter microcirculation, which causes the loss of myelin, axons, and oligodendrocytes by toxic deposition of blood-derived fibrin (ogen) and blood flow reductions [108]. Supporting this idea, it was shown in a recent study that white matter damage evolves in parallel with BMP4 upregulation in pericytes. In fact, BMP4 can induce astrogliogenesis at the

Presently, more and more studies have begun to pay attention to the position of microcirculatory in ischemic stroke. Microvessels are the new targets in ischemic stroke states [83]. As summarized previously, pericytes are important components of cerebral microcirculatory and can regulate microcirculation during and after cerebral ischemia. After ischemic insult, pericytes strongly migrate into the peri-infarct area surrounding the necrotic tissue [84]. Afterwards, the contractile rigor appears and induces segmental narrowing of capillaries, trapping of blood cells and later the death of pericytes [23]. This contraction is persistent, Yemisci et al. showed that pericytes on microvessels contract during ischemia and remain contracted despite reopening of the occluded middle cerebral artery (MCA) [23]. Indeed, pericyte death in rigor will produce a long-lasting decrease of capillary blood flow, as well as a breakdown of the blood-brain barrier, both of which will contribute to ongoing neuronal damage after stroke [30]. Clinically, revascularization and reperfusion therapy shortly after ischemia can improve recovery. Although reperfusion therapy is an important measure to salvage oxygen-starved tissues, it produces paradoxical tissue responses where no reflux of capillaries after perfusion is a common phenomenon [85]. Yemisci et al. have found that ischemia and reperfusion-induced injury to pericytes may impair microcirculatory reflow and negatively affect survival by limiting substrate and drug delivery to tissue already under metabolic stress, despite recanalization of an occluded artery [23]. In addition, pericytes become rigid and die after ischemia, resulting in continuous capillary contraction, thereby limiting the reperfusion of microvessels, which will also lead to no reflow after stroke [86]. It is well known that cerebral ischemia can induce vascular regeneration and occurs immediately after the injury. Many angiogenic mediators, cytokines and growth factors are unregulated in both human and rodent brain ischemia [87]. Moreover, studies using gene expression have revealed significant changes in VEGF/VEGFR, angiopoietin/Tie, PDGF-B/ PDGFR-β, TGF-β, and FGF signaling in a ischemia model in mice [88]. As mentioned previously, pericytes are associated with a variety of angiogenic factors, cytokines and growth factors. Therefore, they may participate in angiogenesis following cerebral ischemia by controlling the formation and maturation of neovascularization. In addition, recent studies have reported that the rapid loss of capillary pericytes after cerebral ischemia is also associated with fibrotic recombination of the ischemic tissue [89]. Fibrotic scar tissue is formed in the lesion site of the central nervous system and is thought to block axonal regeneration, resulting in permanent functional deficits [90]. Currently, multiple pathways are involved in fibrosis. Platelet-derived growth factor (PDGF) signal transduction is one of the central mediators [91]. Fernández-Klett et al. found that after experimental and human stroke the loss of pericytes is accompanied by the proliferation of a novel population of PDGFRβ＋stromal cells, which contributes to the deposition of fibrous ECM [89]. Pericytes, the precursors of myofibroblasts, are a source of pathological matrix collagens. In fact, Leaf et al. have shown that pericytes activate both inflammation and fibrogenesis in response to tissue injury via a TLR- and MyD88-dependent mechanism, leading to tissue damage and extracellular matrix deposition [92]. As is known, the function of pericytes is heterogeneous. Previous research has been proven that type-1 pericytes (Nestin-GFP–/NG2-DsRed+) generate adipocytes and fibroblasts but not neural cells, while type-2 pericytes (Nestin-GFP+/NG2-DsRed+) generate either Tuj1+neural cells or become muscle cells [93,94]. In addition, different subtypes of pericytes respond differentially to tissue 5

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Fig. 2. Brain Perivascular Niche schematic representation: The structure is composed of several stromal cell types including but not limited to endothelial cells, pericytes, astrocytes, microglia, macrophages, fibroblasts [116]; Cancer stem cells (CSCs) is in close contact with the network structure composed of these cells, which are believed to make distinct contributions to tumor survival, invasion and metastasis.

loss-of-function experiments have demonstrated that PDGF-BB-PDGFRβ signaling promotes pericyte–fibroblast transition, both in vitro and in vivo tumors, which significantly contributes to tumor invasion and metastasis [125]. The vascular system of glioma is characterized by microvascular proliferation (MVP), which is the characteristic feature of high-grade glioma [126]. MVP is an abnormal vascular structure, which contains multilayered mitotically active endothelial and smooth muscle cells/ pericytes [127]. Previous studies have confirmed the role of pericytes in tumor MVP. Sun et al. through their study of human glioma tissue samples, have found that pericytes proliferation is one of the significant features of malignant gliomas. In fact, the locally hyperplastic pericytes are the main components of malformed microvessels, which usually shows disordered arrangement, loose connection and active cell proliferation, in malignant gliomas [121]. Xu et al. by using the technique of PCR mRNA arrays and immunohistochemical stains on tissue microarray, have found that in glioblastoma (GBM) microvascular proliferation, the selective expression of PDGFRB protein is present in pericytes, and that the expression level of PDGFRB in GBM microvascular proliferation is significantly higher than that in GBM tumor cells [128].

expense of oligodendrocyte precursor cell proliferation and maturation, thereby aggravating white matter damage [109].

5.3. Brain tumor Previous studies have shown that cancer stem cells(CSCs)are an important cause of radio and chemo resistance in brain tumors [110–112]. A current study has found that the resistance of CSCs to treatment is related to microenvironmental factors existing in the perivascular niche(PVN)(Fig. 2) around cerebral blood vessels [113,114]. Pericytes as important components of PVN have been identified to contribute to the structural stability of PVN in the context of tumor development. Previous studies suggest that pericyte has an important role in shaping the angioarchitecture in the vascular niche of brain tumors, a critical part of the establishment of brain tumor neovascular tree [115]. As discussed previously, pericytes play an important role in normal and pathological angiogenesis, whether in normal tissues or tumors. Relevant studies have confirmed that pericytes recruitment in brain tumors promotes angiogenesis [117] and indirectly contributes to the growth and survival of tumor by regulating angiogenesis. Immature NG2-expression pericytes regulate the proliferation of endothelial cells through sequestration of angiotensin during tumor vascular development, and then play a role in brain tumor angiogenesis [118]. Similarly, in the rat RG2 glioma model, studies have found that RG2 pericytes promote angiogenesis by producing basement membrane as a scaffold for newly forming blood vessels and cause functional abnormalities [119]. On the other hand, abnormal blood vessels with immature and leakage in tumors are related to the structural changes or scantiness of functional pericytes or the perturbed associations between pericytes and endothelial cells [120,121]. Hosono et al. by using the rat RG2 glioma model, have found that desmin-positive pericytes characterized by morphological abnormalities, are abundantly present on leaky vessels [119]. Through the study of NG2 proteoglycan gene, it was found that the loss of pericyte-endothelial cell interaction in melanoma mouse model diminishes formation of endothelial junctions and assembly of the basal lamina [122]. Furthermore, pericytes are also associated with metastasis of tumor tissues. Firstly, pericytes deficiency can lead to immaturity and leakiness of tumor blood vessels, thereby increasing tumor interstitial fluid pressure and enhancing cancer cells flowing into vessels [123]. Besides, Zhang et al. have found that in rat brain U-251 glioblastoma xenografts, malignant pericytes expressing GT198 can proliferate into tumor cells by angiogenesis, and can cause pericyte-derived tumor cells migrate into the lymph nodes [124]. Similarly, Hosaka et al. through Gain-and-

6. Potential of pericyte-based therapy The physiological and pathological mechanisms have not been completely understood, but there is strong evidence about the participation of pericytes in physiological and pathological conditions in vivo, which reveals their extensive therapeutic potential. It is reported that pericytes have contributed substantially to the formation of tissue engineering, and they are the therapeutic targets for regenerated medicine [129,130]. As mentioned previously, pericytes have stem cell-like characteristics, which can be differentiated into cell types from different lineages. Various characteristics and functions of pericytes provide possibility for promoting tissue regeneration and repair, that is why they have been considered and used as a source of tissue engineering [131]. However, due to the heterogeneity of pericytes and their phenotypic and functional differences, their use is greatly limited in clinical trials. At present, their therapeutic potential in regenerative medicine is mainly focused on blood vessels. Pericyte-mediated regulation of vascular stability, angiogenesis and blood flow are well described while their regenerative and immunomodulatory characteristics are still not completely revealed [132]. Certainly, they mainly play an important role in increasing vascular formation and promoting vascular stability. The therapeutic potential of pericytes has been widely studied in the 6

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field of oncology. Pericyte-related anticancer therapy involves different pathways, and mainly includes two aspects. The first is to enhance anticancer drug efficacy using pericyte-overexpression markers. Pericyte-targeting drug delivery is the use of pericytes pecific peptides, small molecules and DNA in tumor therapy [133], which can enhance delivery efficacy of conventional anticancer drug. Number and structure of pericytes in tumor blood vessels determine vascular wall density and the sensitivity to chemotherapeutic drugs and antitumor drug. Existing studies have proved that the reduction of pericytes recruitment and coverage in tumor blood vessels, through related signaling pathways, can increase the accumulation of anticancer molecules or drugs in tumors and improve the effect of anti-cancer therapy [134,135]. The second is to regulate pericyte itself for vascular therapy, including antiangiogenic and vascular normalization therapy. As previously discussed, the pericyte coverage of blood vessels in tumors is heterogeneous and they are a double-edged sword in cancer therapy. In the past, anti-angiogenic therapies was the main treatment of pericyte-related tumors therapy [123]. However, vascular normalization therapy restoring the normal function of blood vessels is an emerging cancer treatment strategy [136]. Therefore, it is evident that the key to the pericyte-targeted therapy is to achieve a balance between pro-angiogenic and anti-angiogenic functions. Pericytes are multipotent cells present in every vascularized tissue of the body. In addition to tumors, pericyte-therapy also involves heart, retinal, bone, skin, etc. Katare et al. transplanted saphenous vein derived pericyte progenitor cells (SVPs) into a mouse myocardial infarction (MI) model, and it was observed that SVPs improves the repair of infracted heart through activation of an angiogenic program involving micro-RNA-132 [137]. On the other hand, Mendel et al. research have found that adipose-derived stem cells derived pericytes can integrate with retinal vasculature, and provide functional vascular protection in multiple murine models of retinal vasculopathy by promoting angiogenesis and vascular support [138]. Furthermore, in skin injury model rats, adipose-derived stem cells derived pericytes can play a supportive role in the formation of vascular structures in the healing wound [139]. Similarly, in a mouse model for critical size bone injury, adipose-derived stem cells derived pericytes generate osteoblasts, to colonize cancellous bone scaffolds and contribute to regeneration [140]. To date, the study of pericyte transplantation in ischemic stroke has not been reported, although the important protective role of pericytes in the pathological process of ischemic stroke has been confirmed. Consequently, further in-depth studies of pericyte transplantation into ischemic brain are needed.

pericytes and determining their phenotypes and functions are the key to further development of clinical application of them. Declaration of Competing Interest The authors declare no conflict of interest. Acknowledgments This work has been supported by the National key research and development plan (2018YFC170500) and the Tianjin major chronic disease research project (16ZXMJSY00040). References [1] D.E. Sims, The pericyte–a review, Tissue Cell 18 (2) (1986) 153–174. [2] A. Armulik, G. Genove, C. Betsholtz, Pericytes: developmental, physiological, and pathological perspectives, problems, and promises, Dev. Cell 21 (2) (2011) 193–215. [3] D.A. Hartmann, R.G. Underly, R.I. Grant, A.N. Watson, V. Lindner, A.Y. Shih, Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice, Neurophotonics 2 (4) (2015) 041402. [4] M. Krueger, I. Bechmann, CNS pericytes: concepts, misconceptions, and a way out, Glia 58 (1) (2010) 1–10. 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7. Conclusions and prospects In summary, pericytes are truly pluripotent cells, and the density of pericytes is the highest in the brain. Therefore, they probably play many roles that are critical for cerebral vascular stability. In this review, the functions and mechanisms of pericytes in brain-associated vascular disease were summarized. As a matter of fact, pericytes play a variety of functions in stroke, dementia and brain tumors by regulating blood flow, stabilizing blood-brain barrier, promoting neovascularization and regulating neuroinflammation. Clearly, in the recent years, the research on pericytes’ physiological and pathological function has greatly increased. However, an iterated concern in cell biology is to define the different types of pericytes. In fact, pericytes will show different functions according to their different physiological and pathological stages and conditions, that is why the description and definition of them will inevitably change. They include its different subtypes, suggesting diversity of function. For example, as discussed before, pericytes can regulate blood flow. However, some publications question the regulation of pericytes on capillary blood flow [141]. These differences may be related to experimental differences, but they may also be due to the heterogeneity of pericytes and confusion about cell identities. Therefore, determining the heterogeneity of 7

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