Vascular fibrosis in atherosclerosis

Cardiovascular Pathology xxx (2013) xxx–xxx

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Cardiovascular Pathology

Review Article

Vascular fibrosis in atherosclerosis Tao-Hua Lan a, b, Xiong-Qing Huang c, Hong-Mei Tan a,⁎ a

Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, PR China Department of Cardiology, Guangdong Provincial Hospital of Chinese Medicine (postdoctoral mobile research station of Guangzhou University of Traditional Chinese Medicine), Guangzhou, 510006, PR China c Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, PR China b

a r t i c l e

i n f o

Article history: Received 19 October 2012 Received in revised form 10 December 2012 Accepted 8 January 2013 Available online xxxx Keywords: Atherosclerosis Fibrosis Pathogenesis Signal transduction Risk factors

a b s t r a c t Vascular fibrosis, characterized by reduced lumen diameter and arterial wall thickening attributable to excessive deposition of extracellular matrix (ECM), links with many clinical diseases and pathological progresses including atherosclerosis. It involves proliferation of vascular smooth muscle cell (VSMC), accumulation of ECM and inhibition of matrix degradation. The risk factors associated with cardiovascular disease, including hypertension, hyperglycemia, dyslipidemia and hyperhomocysteinemia (HHcy), are also suggested as initiation and progression factors of vascular fibrosis. Vascular fibrosis has been found to relate to renin-angiotensin-aldosterone system (RAAS), oxidative stress, inflammatory factors, growth factors and imbalance of endothelium-derived cytokine secretion. Angiotensin II (Ang II) and aldosterone, the circulating effector hormones of RAAS, are recognized as responsible for the pathophysiology of vascular fibrosis. Transforming growth factor-beta (TGF-beta) plays a critical role in ECM accumulation and vascular remodeling via up-regulating the production of several agents including connective tissue growth factor (CTGF) and fibroblast growth factor. An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) results in collagen accumulation and adverse matrix remodeling. Aberrant expression or function of peroxisome proliferator-activated receptor gamma (PPAR gamma) is also associated with, and very likely contributes to, the progression of pathological fibrosis and vascular remodeling. In this review, we discuss the pathogenesis of vascular fibrosis in atherosclerosis with focus on the networking among main responsible mediators. The main pathophysiologic factors leading to vascular fibrosis will also be discussed. © 2013 Elsevier Inc. All rights reserved.

1. Introduction Cardiovascular diseases comprise one of the most frequent causes of worldwide mortality. Atherosclerosis, which is one of the primary causes of the development of cardiovascular disease, is accepted to be associated with vascular fibrosis. Vascular fibrosis involves accumulation of extracellular matrix (ECM) proteins, particularly collagen and fibronectin in the vascular media and contributes to structural remodeling and scar formation [1]. Arterial stiffening or remodeling is now fully recognized as an important consequence of vascular fibrosis This work was supported by National Natural Science Foundation of China (Grant No. 30600250 and No. 81202815), Natural Science Foundation of Guangdong province of China (Grant No. 10151008901000146), the Fundamental Research Funds for the Central Universities (Grant No. 10ykpy33) and Scientific Research Funds for the Returned Overseas Chinese Scholars from the Ministry of Personnel (2006,164#). ⁎ Corresponding author. Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, PR China. Tel.: +86 20 87330028; fax: +86 20 87330026. E-mail address: [email protected] (H-M. Tan).

that has been shown to promote the development of atherosclerosis [2]. The intercellular networking that occurs among smooth muscle cells (SMCs), macrophages, T lymphocytes and endothelial cells leads to a fibroproliferative response, in which ECM plays an important role [3]. The biomechanical properties of vessels, particularly of the major arteries and veins, are largely dependent on the absolute and relative quantities of collagens and elastin [4,5]. A lack of elastin or excessive collagen in the vascular wall leads to vascular fibrosis and increased stiffness [6]. Studies suggested the risk factors associated with cardiovascular disease, including hypertension, hyperglycemia, dyslipidemia, and hyperhomocysteinemia (HHcy), as initiation and progression factors of vascular fibrosis. Vascular fibrosis has been found to relate to reninangiotensin-aldosterone system (RAAS), transforming growth factorbeta (TGF-beta), connective tissue growth factor (CTGF), matrix metalloproteinases (MMPs) and peroxisome proliferator-activated receptor gamma (PPAR gamma) (Fig. 1). This chapter reviews the main risk factors and pathogenesis of vascular fibrosis and outlines the networking among the main responsible mediators.

1054-8807/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.carpath.2013.01.003

Please cite this article as: Lan T-H, et al, Vascular fibrosis in atherosclerosis, Cardiovascular Pathology (2013), http://dx.doi.org/10.1016/ j.carpath.2013.01.003

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and promotes endothelial dysfunction and structural remodeling. Mechanical stretching induced CTGF, and increased immunoreactive Ang II. TGF-beta is expressed during vascular remodeling induced by hypertension and regulates collage matrix deposition on the arterial wall [15,16]. The MMP/TIMP system also plays a determinant role in the regulation of collagen tissue turnover in hypertensive patients [10]. Hypertension-associated vascular disease is also an inflammatory process. Oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration and fibrosis, which are important processes involved in vascular remodeling in hypertension [17]. 2.2. Hyperglycemia

Fig. 1. Pathogenesis and risk factors of vascular fibrosis in atherosclerosis. Atherosclerosis, which is one of the primary causes of the development of cardiovascular disease, is accepted to be associated with vascular fibrosis. Vascular fibrosis involves proliferation of VSMC, accumulation of ECM and inhibition of matrix degradation. Hypertension, hyperglycemia, dyslipidemia, and HHcy represent noxious factors for the vascular fibrosis in atherosclerosis by promoting various mechanisms of the fibrogenic process, including RAAS activation, TGF-beta and CTGF expression, imbalance between MMP and TIMP, aberrant expression of PPAR gamma. CTGF, connective tissue growth factor; ECM, extracellular matrix; HHcy, hyperhomocysteinemia; MMPs, matrix metalloproteinase; PPAR gamma, peroxisome proliferatoractivated receptor gamma; RAAS, renin-angiotensin-aldosterone system; TGF-beta, transforming growth factor-beta; TIMPs, tissue inhibitors of metalloproteinases; VSMC, vascular smooth muscle cell.

2. Risk factors for vascular fibrosis There are several known risk factors that can lead to cardiovascular disease, among which, hypertension, hyperglycemia, dyslipidemia, and hyperhomocysteinemia (HHcy) are thought to be associated with initiation and progression of vascular fibrosis. In this section, we discuss our current understanding of the four main pathophysiologic factors, especially their roles in vascular fibrosis. 2.1. Hypertension Hypertension is associated with vascular remodeling, which, among other alterations, is characterized by an increase in ECM content, especially fibrillar collagen type I [7]. In vivo experiments have shown that chronic pressure overload stimulates both procollagen gene expression and collagen protein synthesis [8,9]. Previous study also suggested that systemic extracellular degradation of collagen type I is depressed in patients with essential hypertension [10]. Active collagen synthesis, in combination with depressed degradation of collagen, may facilitate vascular fibrosis in hypertensive patients. Principally, mechanical factors (wall shear stress, wall circumferential stress) and hypoxia determine hypertensive vascular remodeling [11]. The vascular wall undergoes functional, mechanical and structural changes in response to hemodynamic or biomechanical stress in hypertensive patients [12]. At the molecular level, numerous factors have been implicated in the vascular remodeling of hypertension including activation of the RAAS, imbalance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), CTGF up-regulation and aberrant G protein-coupled receptor signaling [13,14,10]. Among the many factors involved in the hypertensive vascular phenotype, Ang II is especially important. Ang II augments vascular inflammation

One pathological response to tissue injury of chronic hyperglycemia is the development of fibrosis, which involves predominant ECM accumulation [18]. Increased deposition of matrix proteins within the diabetic vessel wall was described several decades ago. Expansion of ECM with fibrosis occurs in many tissues as part of the end-organ complications in diabetes [19]. In diabetes, vascular remodeling extends to capillaries, microvascular beds, and arteries of different calibre. In animal models of Type 2 diabetes, it has been found that increased intimal proliferation and medial thickness as well as ECM deposition occur in vessels such as mesenteric arteries and aorta [20]. The mechanisms of hyperglycaemia-induced vascular remodeling are incompletely understood, but metabolic and mechanical factors seem to play an important role. Hyperglycemia can work through both metabolic and hemodynamic pathways to change growth factors and ECM turn-over [19]. Chronic hyperglycemia accelerates the reaction between glucose and proteins and leads to the formation of advanced glycation end products (AGE), which form irreversible cross-links with many macromolecules such as collagen and, hence, alter arterial mechanical properties [19,21]. AGE not only structurally stiffen structural collagen backbones but also act as agonists to AGE receptors on various cell types, which stimulate the release of profibrotic growth factors such as TGF-beta, promote collagen deposition, increase inflammation, and ultimately lead to tissue fibrosis [22–24]. In addition, AGE can reduce the activity of MMPs, a family of endopeptidases involved in matrix degradation [25,26]. A classic hallmark of diabetes pathology is the activation of the intrarenal renin-angiotensin system [18]. High glucose enhances Ang II response, through up-regulation of the Ang II AT1 receptor, and enhanced ROS production [27,28]. High glucose milieu of diabetes increases Ang II production by renal, and especially mesangial cells, which results in stimulation of TGF-beta secretion and leads to increased synthesis and decreased degradation of matrix proteins, thus producing matrix accumulation [29]. It has been suggested that CTGF is a potent inducer of ECM in diabetes [30]. 2.3. Dyslipidemia Dyslipidemia is a conventional risk factor for atherosclerosis. Abnormalities in lipid metabolism appear to play a pathogenic role in progressive tissue fibrosis [31–33]. More and more data have accumulated that high-cholesterol diet was sufficient to induce intrarenal inflammation, vascular remodeling, and perivascular and tubulointerstitial fibrosis [34–36]. Increase of collagen I, collagen III, collagen IV, fibronectin and tenascin and altered matrix degradation play a role in the interstitial fibrogenesis in hypercholesterolemic rats [31,32]. Diet-induced hypercholesterolaemia resulted in a simultaneous increase in ECM deposition and blunted MMPmediated degradation, overall promoting perivascular and tubulointerstitial fibrosis, which was reversible by lipid-lowering dietary interventions [33]. It is thought that an increase of lipids within the vasculature leads to an increase in reactive oxygen species as well as an increase in the

Please cite this article as: Lan T-H, et al, Vascular fibrosis in atherosclerosis, Cardiovascular Pathology (2013), http://dx.doi.org/10.1016/ j.carpath.2013.01.003

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oxidation of low-density lipoproteins (LDL). This increase in oxidative stress may cause endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, and fibrosis, which are important processes involved in vascular remodeling [17]. Previous study demonstrated hypercholesterolemia increased circulating levels of oxidized LDL (Ox-LDL), which can promote fibrosis by stimulating synthesis and expression of TGF-beta [33,37,38]. Increased TGF-beta expression in the hypercholesterolemic kidney is accompanied by up-regulation and activation of its Smad effectors, underscoring fibrogenic activity [33]. 2.4. Hyperhomocysteinemia (HHcy) HHcy, elevated plasma homocysteine, has been recognized as an independent cardiovascular risk factor which may alter vascular structure [39]. McCully's first reported that the accumulation of collagen in atherosclerotic plaques in children with premature atherosclerosis resulted from severe HHcy [40]. The premature vessels or the injured vessels were susceptible to homocysteine-mediated vascular wall thickening. Previous study reported that HHcy increased collagen accumulation in carotid artery in mice and rats [41]. Homocysteine was also reported to promote vascular SMC proliferation, increase collagen expression in cultured vascular SMC and in atherosclerotic plaques in apolipoprotein E knockout mice [42,43]. Moderate HHcy is associated with an increased incidence of carotid artery stenosis in humans [44]. We previously reported that HHcy promoted post-injury neointima formation and led to luminal narrowing [45]. Besides the cardiovascular system, HHcy also plays a role in renal and hepatic fibrosis. Arterial and arteriolar wall thickening and focal tubulointerstitial fibrosis were also found in the kidneys of the hyperhomocysteinemic rats [46]. Hyperhomocysteinemic patients develop perivascular hepatic fibrosis and homocysteine has been shown to be the key mediator of methionine metabolism deficiency in the development of hepatic fibrosis [47]. Imbalance between MMPs and TIMPs has been implicated in the vascular remodeling of HHcy. An increase in MMPs expression and enhanced activity of MMP-2 were found in HHcy aorta and in cultured human vascular smooth cells [48,49]. There is a correlation between the increase in plasma homocysteine level (above 15 μM) and the increase in hepatic MMP-2 activity [47]. HHcy in cystathionine β synthase deficiency mice promotes oxidative stress, which may cause mitochondrial damage in association with activation of hepatic stellate cells, leading to fibrosis, and steatosis in liver [50]. Homocysteine induced impairment of paraoxonase-1 (PON1) gene expression and activity in liver of hyperhomocysteinemic mice [51]. PON1 hydrolyzes oxidized cholesteryl esters and phospholipids in oxidized lipoproteins, thereby inhibiting the lipid peroxidation products from binding the LDL [52]. PON1 also plays a major role in the protective role of HDL against coronary artery disease [53]. Previous results found that homocysteine enhanced expression of LOX-1 in cultured aortic endothelial cells, in HHcy mice and as well as in HHcy human mononuclear cells, which can increase Ox-LDL uptake leading to promote fibrosis [54–56]. 3. Pathogenesis for vascular fibrosis (Fig. 2) 3.1. Renin-angiotensin-aldosterone system (RAAS) and vascular fibrosis RAAS has emerged as one of the essential links in the development of vascular remodeling of the heart and systemic organs [57]. Angiotensin II (Ang II) and aldosterone, the circulating effector hormones of RAAS, are recognized as responsible for the pathophysiology of vascular fibrosis. The molecular mechanism of Ang II and aldosterone in the regulation of vascular fibrosis has drawn considerable attention.

Fig. 2. Networking among the main responsible mediators of vascular fibrosis. Vascular fibrosis has been found to relate to RAAS system [including Ang II, aldosterone], TGFbeta, CTGF, MMPs and PPAR gamma. Ang II promotes vascular fibrosis through direct effects or via induction of TGF-beta and CTGF. Ang II was also showed to increase MMPs and aldosterone production which promotes fibrosis. Second to Ang II, several mechanisms may account for the ability of aldosterone to promote fibrosis and collagen formation, mainly including up-regulation of Ang II receptors, stimulation of TGF-beta and CTGF synthesis, stimulation of MMPs activity. Believed as the most important ECM regulator, TGF-beta plays a critical role in vascular fibrosis via upregulating the production of CTGF. MMPs (such as MMP-2 and -9) enhance the release of TGF-beta, and TGF-beta up-regulates the expression of MMP-2 and MMP-9. CTGF is a downstream mediator of Ang II-induced TGF-beta up-regulation on ECM regulation and fibrosis. MMPs activation leads to weakening of the vessel wall, and an imbalance between MMPs and TIMPs results in collagen accumulation, adverse matrix remodeling and reactive interstitial fibrosis. Aberrant expression or function of PPAR gamma is associated with the progression of pathological fibrosis and vascular remodeling. PPAR gamma abrogates the secretion of TGF-beta and CTGF. There is an inverse relationship between PPAR gamma expression levels and fibrogenesis. ACE, angiotensin converting enzyme; Ang II, Angiotensin II; CTGF, connective tissue growth factor; ECM, extracellular matrix; MMPs, matrix metalloproteinase; PPAR gamma, peroxisome proliferator-activated receptor gamma; RAAS, renin-angiotensin-aldosterone system; TGF-beta, transforming growth factor-beta; TIMPs, tissue inhibitors of metalloproteinases.

Ang II, the principal effector hormone of the RAAS, not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation, but is also generally accepted as a growth factor that regulates many processes implicated in vascular pathophysiology, including cell growth/apoptosis of vascular cells, migration of VSMCs, inflammatory responses and ECM remodeling [58]. Ang II acts through its binding to two main specific receptors, AT1 and AT2. Activation of AT1 receptor is present in most of the Ang II-mediated cardiovascular responses, such as vasoconstriction, hypertrophic effects, fibrosis and inflammation. Once Ang II binds to the AT1 receptor, it activates a series of signaling cascades, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), insulin receptor, c-Src family kinases, Ca 2+dependent proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK) and Janus kinases (JAK), which in turn regulate the Ang II pathologic effects in the vasculature [59]. AT1 receptor also implicated in cell growth and hypertrophy by activating PKC and MAPKs, including ERK1/2, p38 MAPK, and c-Jun NH2-terminal kinase (JNK) [60]. Ang II-mediated EGFR activation occurs in a Src-dependent and redox-sensitive manner, and also via calcium-dependent and-independent pathways [61,62]. Evidence shows that Ang II stimulated the phosphorylation of PDGF-β receptor (PDGFβ-R) via the binding of tyrosine-phosphorylated Shc to PDGFβ-R [63]. Ang II has also been shown to increase serine phosphorylation of the insulin receptor βsubunit, causing insulin receptor substrate (IRS-1) inactivation both by uncoupling it from downstream effectors (PI3K, PDK1, Akt) and by targeting it for degradation in the proteasomal pathway [64,65]. Ang II promotes cellular proliferation and ECM synthesis which lead to vascular fibrosis through direct effects or via induction of several mediators, including TGF-beta, CTGF, cytokines (IL-6,TNF-alpha), and monocyte chemoattractant protein type 1 (MCP-1). It is generally accepted that Ang II-induced ECM production is mainly mediated by

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up-regulation of the profibrotic factor TGF-beta and its downstream mediator CTGF [66,67]. Ang II, through PKC and p38 MAPK-dependent pathways, activates the binding of nuclear proteins to the binding site of the activator protein-1 (AP-1) of the TGF-beta1 promoter. However, recent studies have showed that Ang II induces CTGF expression via the TGF-beta–independent Smad signaling pathways [68,69]. Ang II was showed to increase MMPs production involved in matrix degradation which leads to weakening of the vessel wall. Ang II also stimulates aldosterone production which promotes fibrosis and collagen formation [70]. Aldosterone, the release of which is stimulated by angiotensin II, is the primary effector hormone of the RAAS only second to Ang II. Several mechanisms may account for the ability of aldosterone to promote fibrosis and collagen formation, mainly including upregulation of Ang II receptors, stimulation of TGF-beta and CTGF synthesis, stimulation of MMPs activity, and participation in VSMC hypertrophy and endothelial dysfunction [71]. Besides the wellknown effect of Ang II in stimulating aldosterone production from the adrenal cortex, aldosterone results in an increase of Ang II binding [72] and potentiation of the Ang II hypertrophic response [73]. Aldosterone was also showed to increase cardiac AT1 density and gene expression, and the increased cardiac AT1 density could be prevented by the aldosterone antagonist spironolactone [74]. Aldosterone treatment might decrease AT2 gene expression which enhances the AT1 receptor activation–induced Ang II fribrogenic effect [75]. In addition, the enhanced expression of ACE and TGF-beta can been found in aldosterone–treated rats [76]. It has also been reported that aldosterone stimulates the expression of plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of plasminogen activators which is implicated in ECM accumulation by inhibiting matrix degradation, and induced CTGF expression via both p38 MAPK cascade and mineralocorticoid receptor [77,78]. Aldosterone induces MMP activity in adult rat ventricular myocytes via activation of the mineralocorticoid receptor, PKC, and reactive oxygen species (ROS)-dependent activation of the MEK/ERK pathway [79]. 3.2. Transforming growth factor-beta (TGF-beta) and vascular fibrosis Transforming growth factor (TGF)-beta is a ubiquitously expressed cytokine that belongs to a large superfamily, of which, TGF-beta1 is most frequently up-regulated in ECM remodeling [80]. TGF-beta signals through a heteromeric cell-surface complex of two types of transmembrane serine/threonine kinases, type I receptors and type II receptors [81]. Type I receptors phosphorylation, which is activated by type II receptors, is essential for the activation of downstream target proteins [82]. TGF-beta predominantly transmits the signals through cytoplasmic proteins called Smads, which translocate into the cell nucleus acting as transcription factors [83]. The Smad signal transducers consist of receptor-activated (R-) Smads (Smad1, -2,-3,-5 and -8), common-partner (Co-) Smads (Smad4) or inhibitory (I-) Smads (Smad6 and -7) that mediate transcription of target genes [84]. Smad2 and Smad3 are specific mediators of TGF-beta/activin pathways, whereas Smad1, Smad5 and Smad8 are involved in bone morphogenetic protein (BMP) signaling (especially BMP-7) which inhibits VSMC proliferation via I-Smad (Smad6 and Smad7) activation [85]. However, studies have shown that overexpression of Smad6 may selectively inhibit BMP receptor signaling whereas Smad7 inhibits both BMP and TGF-beta/activin receptor signaling [86]. Smad7 expression, resulting in the inhibition of TGF-beta-induced fibronectin, collagen and CTGF expression, can also be induced by activation of the EGF receptor, IL-gamma signaling through signal transducer and activator of transcription (STAT), and TNF-alpha induced activation of NF-Κb [87,88]. In addition to the Smad pathway, growing biochemical and developmental evidence supports that non-Smad pathways also

participate in TGF-beta signaling and serve as nodes for crosstalk with other major signaling pathways [89,90]. The JNK/p38, Erk/MAPK, Rho-like GTPase, and PI3/Akt pathways are believed to reinforce, attenuate or modulate downstream cellular responses possibly accounting for the varying effects of TGF-beta [91]. These non-Smad pathways may have significant interactions with the Smad pathway to further explain TGF-beta's diverse functions [92]. TGF-beta participates in the pathogenesis of many cardiovascular diseases, including hypertension, restenosis, atherosclerosis, cardiac hypertrophy, and heart failure. Believed as the most important ECM regulator [93], TGF-beta plays a critical role in ECM accumulation and vascular remodeling via up-regulating the production of several agents, including growth factors (CTGF, FGF), related gene (c-myc, cjun, junBJI, p53) and PAI-1 [94–97]. Angiotensin II, mechanical stress, endothelin-I, high glucose, extremes of temperature and pH, steroids, and reactive oxygen species have been found to stimulate TGF-beta activation as a mediator of vascular fibrosis [98,99]. Additionally, MMPs (such as MMP-2 and -9) enhance the release of TGF-beta, and TGF-beta can stimulate TIMP resulting in the inhibition of ECM degradation which further induces ECM accumulation and vascular remodeling [100]. 3.3. Connective tissue growth factor (CTGF) and vascular fibrosis CTGF, is a novel and potent profibrotic growth factor that is implicated in fibroblast proliferation, cellular adhesion, angiogenesis, and ECM synthesis [14]. It has been reported that CTGF promotes VSMC proliferation, migration, and production of ECM which may play a role in the development and progression of atherosclerosis [101]. CTGF expression is regulated by several agents, including TGFbeta, TNF-alpha, cAMP, high glucose, dexamethasone, factor VIIa, and mechanical stress [102]. It has been postulated that CTGF is a downstream mediator of Ang II-induced TGF-beta up-regulation on ECM regulation and fibrosis [103,104]. TGF-beta-induced CTGF production is involved with several signal pathways, including Smads, Ras/MEK/ Erk, Ap-1/JNK, PKC, and Tyr [105]. CTGF expression can be decreased by TNF-alpha, cAMP, PGE2, IL-4 and PPAR through TGF-beta down-regulation [106]. CTGF also appears to increase the expression of MMP-2 which is not accompanied by a corresponding increase of TIMP-2 in VSMC culture via AP-1 activation [107]. The addition of CTGF to primary mesangial cells induced fibronectin production, cell migration, and cytoskeletal rearrangement which were associated with recruitment of Src and phosphorylation of p42/ 44 MAPK and protein kinase B [108]. 3.4. Matrix metalloproteinase (MMPs) and vascular fibrosis The matrix metalloproteinases (MMPs) include the collagenases (MMP-1, MMP-8, MMP-13), the gelatinases (MMP-2 and MMP-9), the stromelysins (MMP-3, -10, and -11) and the membrane-type MMPs (MT-MMPs) [109]. Collagenases cleave fibrillar collagens I, II, and III falling apart into gelatins, while gelatinases degrade gelatins and also type IV collagen in basement membranes. Stromelysins are active against a broad spectrum of ECM components, including proteoglycans, laminins, fibronectin, vitronectin, and some types of collagens, while MT-MMPs degrade several ECM components and are also able to activate other MMPs. MMPs, together with cysteine proteinases, aspartic proteinases, and serine proteinases are proteolytic enzymes involved in ECM and basement membranes (BMs) degradation. MMPs play important roles in the physiology of fibrosis, as in liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, and multiple sclerosis. MMPs are thought to mediate the progression of stable atherosclerotic lesions to an unstable phenotype that is prone to rupture through the destruction of strength-giving ECM proteins. MMP-1, MMP-2, MMP-3 and MMP-9 participate in weakening the connective tissue matrix in

Please cite this article as: Lan T-H, et al, Vascular fibrosis in atherosclerosis, Cardiovascular Pathology (2013), http://dx.doi.org/10.1016/ j.carpath.2013.01.003

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the intima, which leads to plaque rupture, acute thrombosis, and SMC proliferation and migration [110]. MMP degradation of EC basement membrane during diapedesis of inflammatory cells could contribute to a decreased endothelial barrier function with increased influx of plasma proteins. All of these interactions have been shown to increase production of MMPs in macrophages which may also provide stimuli for MMP production in neighboring cells and mechanisms for activation of secreted MMP zymogens resulting in developing atherosclerotic lesions that may facilitate further structural changes and enable their growth [25]. The expression of most MMPs is up-regulated during certain physiological and pathological remodeling processes, and mediated by a variety of inflammatory cytokines, hormones, and growth factors, such as IL-1, IL-6, TNF-alpha, EGF, PDGF, basic fibroblast growth factor (bFGF), and CD40 [111–113]. TGF-beta up-regulates the expression of MMP-2 and MMP-9, while decreases the expression of MMP-1 and MMP-3 [114]. Fully activated MMPs can be inhibited by tissue inhibitors of metalloproteinases (TIMPs). An imbalance between myocardial MMPs and TIMPs results in collagen accumulation, adverse matrix remodeling and reactive interstitial fibrosis [115]. 3.5. Peroxisome proliferator-activated receptor gamma (PPAR gamma) and vascular fibrosis There are three PPAR family members [PPAR alpha, PPAR delta (also called PPAR beta), PPAR gamma], of which, PPAR gamma is most extensively studied. Recent reports provide evidence that aberrant expression or function of PPAR gamma is associated with, and very likely contributes to, the progression of pathological fibrosis and vascular remodeling [116]. The molecular mechanisms underlying the antifibrotic effects of PPAR gamma have drawn great attention in recent. The antagonistic effects of PPAR gamma on abrogating TGFbeta induced stimulation of collagen and fibronectin synthesis and the secretion of fibrotic growth factors including TGF-beta and CTGF revealed the antifibrotic role of PPAR gamma in fibrogenesis [117,118]. It was observed that PPAR gamma abrogates Smaddependent collagen stimulation by targeting the p300 transcriptional coactivator [119]. The PPAR gamma-independent pathways might also involve in the antifibrotic effects triggered by PPAR gamma ligands, including inhibition of fibroblast migration, adipocyte differentiation and myofibroblast transition. As a hitherto, PPAR gamma is unsuspected nexus between metabolism and pathological fibrosis and vascular remodeling. 4. Pharmacological intervention on vascular fibrosis Some of the marketing drugs used for cardiovascular disease, such as ACE inhibitor, angiotensin receptor blocker and statins, have showed their beneficial effects on prevention of fibrosis. It is now evident that blockade of the RAAS seems to be particularly effective in reducing vascular stiffness and collagen content in human and animal models [120,121]. Statins was shown to reduce accumulation of extracellular matrix and fibrosis via inhibition of expression and activation of small guanosintriphosphate-binding proteins such as Ras and Rho [122,123]. However, future experimental studies and clinical trails targeting the mentioned signaling events are in great need for finding promising therapeutic approaches in reducing vascular fibrosis associated with cardiovascular diseases. 5. Summary Atherosclerosis is a pathological process that underlies the development of cardiovascular disease, and vascular fibrosis is accepted to be one of the primary causes of the development of atherosclerosis. Hypertension, hyperglycemia, dyslipidemia, and HHcy represent nox-

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ious factors for vascular fibrosis in atherosclerosis by promoting various mechanisms of the fibrogenic process. A combination of these factors may further aggravate the progression of vascular fibrosis, while aggressive control of blood pressure, blood glucose, dyslipidemia and plasma homocysteine level helps to slow the progression [18,124]. This review outlined the intricate interaction among five most researched mediators which play important roles in the pathogenesis of vascular fibrosis. In addition, there are other mediators that showed potential role in the development of vascular fibrosis, such as NADPH oxidases. NADPH oxidase (Nox) enzymes, important sources of reactive oxygen species, participate in VSMC proliferation and fibrosis, which contribute to vascular pathologies including atherosclerosis [125]. Therefore, future studies are expected to improve the understanding of the pathogenesis of vascular fibrosis. References [1] Touyz RM. 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