regulation of matrix proteins and impact on vascular structure

Regulation of Matrix Proteins and Impact on Vascular Structure

José Tuñón, MD, Marta Ruiz-Ortega PhD*, and Jesús Egido, MD*

AddressDepartments of Cardiology and Vascular Pathology (*), Universidad Autónoma, Fundación Jiménez Díaz, Avda. Reyes Católicos 2, 28040 Madrid, Spain.

E-mail: [email protected]

Current Hypertension Reports 2000, 2:106–113Current Science Inc. ISSN 1522–6417Copyright © 2000 by Current Science Inc.

IntroductionThe vascular extracellular matrix (ECM) is composed ofcollagen and elastic fibers embedded in a gel integrated byproteoglycans, hyaluronate, and glycoproteins. Thesemolecules are responsible for the mechanical properties ofthe vascular wall, because they confer tensile strength,compressibility, and elastic recoil. These qualities arerelevant to the normal function of the vessel and must alsobe taken into account in pathologic conditions. Forexample, instantaneous vascular elastic recoil may lead tothe failure of balloon angioplasty in coronary arterydisease and may require the use of a stent.

In addition to its role in the physical properties of thevessels, ECM is involved in biologic processes such ascellular adhesion, proliferation, and migration, that have aspecial relevance in vascular disease. Also, ECM bindsplasma lipoproteins, cytokines, enzymes, and growthfactors, modulating vessel wall metabolism. Then, ECM

behaves as a biologically active system rather than a merekeeper of the vascular structure.

Maintaining an adequate balance of ECM componentsis necessary for the normal functioning of the vasculature.This balance is achieved by the regulation of synthesis andturnover of the different ECM components. Recent publica-tions have reviewed the mechanisms that control growthand matrix production by vascular smooth muscle cells(VSMC) [1••]. Therefore, in this article we approach sev-eral aspects related to the role of ECM in two importantclinical conditions, the stability of atherosclerotic plaquesand hypertension.

Extracellular Matrix and Plaque StabilityRole of extracellular matrix in fibrous cap strengthIn the atherogenic process, there is an increase in ECMsynthesis. Following endothelial dysfunction with lipidtrapping and monocyte recruitment, endothelial injurydue to enzymes, superoxide anions, and other toxicsubstances released by foam cells at death occurs. As aconsequence, subendothelial collagen is exposed to theblood, and platelets adhere to the vascular wall. Thesecells, along with resident cells, release growth factors thatstimulate the migration and proliferation of VSMC thatcover the lipid nucleus. The VSMC suffer a change from acontractile to a secretor phenotype and produce ECM,forming the fibrous cap of the atherosclerotic lesion. Thisproduction of ECM is then part of the atherogenic processand could be seen as an undesirable phenomenon.However, it must also be regarded as a protective reactionof the vessel wall, included in the inflammatory responseagainst the accumulated lipid that is trying to encapsulateand isolate it. The predominating ECM in the fibrous cap isthe collagen, which confers resistance on the hemo-dynamic forces, avoiding plaque rupture. Should thisrupture occur, the lipid nucleus of the lesion is exposed tothe blood and triggers thrombus formation that mayocclude the vessel, leading to an acute coronary event.Then, a reduction in the amount of collagen present in thefibrous cap makes plaques vulnerable to rupture [2••]. Adecrease in collagen may be due to enhanced destructionby collagenolytic enzymes, a reduced production byVSMC, or both.

In recent years, there have been considerable advancesin our understanding of the regulation of ECM in athero-

The vascular extracellular matrix is responsible for the mechanical properties of the vessel wall and is also involved in biologic processes such as cellular adhesion, regulation, and proliferation. Thus, an adequate balance of its compo-nents is necessary for the normal functioning of the vascula-ture. Vascular disorders affect this balance, and this plays a key role in their pathophysiology. Atherogenesis is accompa-nied by an increase in matrix deposition in response to low-density lipoprotein accumulation. However, this matrix, mainly collagen, also has a protective role by forming a fibrous cap around the lipid core, avoiding contact with blood. A decrease in the amount of collagen will weaken the cap and make it prone to rupture, leading to thrombosis and acute coronary syndromes. In hypertension, the increase in matrix deposition results in vascular stiffness and cardiac dysfunction. In this paper, we discuss the relevance of matrix regulation in these conditions.

Regulation of Matrix Proteins and Impact on Vascular Structure • Tuñón et al. 107

sclerotic plaque. It has been demonstrated that unstablplaques display greater macrophage infiltration than stableones. These cells are now accepted to destabilize plaquesby degrading ECM [2••]. In accordance with this, it hasbeen observed that active metalloproteinases (MMP) arepresent in atherosclerotic lesions and that atheroma-richhuman carotid plaques display greater amounts of MMP-1and MMP-13 than fibrous ones [2••,3]. In fact, it has beenconfirmed that human monocytes display collagenolyticactivity when incubated with fibrous caps from humanatherosclerotic lesions in vitro [4]. This activity dis-appeared in the presence of an MMP inhibitor. Lipid levelreduction in experimental models of atherosclerosis habeen shown to decrease the inflammatory infiltrates ofmacrophages [5•,6] and the activity of MMP-2, MMP-3,and MMP-9, resulting in an increase in collagen content ofthe lesions when this situation persists over several months[5•]. This reduction in the inflammatory infiltrate is due, atleast in part, to a diminution of the expression of chemo-attractant protein-1 (MCP-1), secondary to a decrease inthe activity of the transcription factor NF-kB [6] (Fig. 1).This factor seems to be of capital importance in athero-sclerosis, because it controls the expression of severalmediators involved in cell recruitment into the vessel wall[7••] and also has direct implications for the regulation ofECM by controlling the expression of MMP-9 by macro-phages [8]. Besides being degraded by the action of inflam-matory cells, ECM participates in the regulation ofrecruitment of these cells into the vessel wall. Accordingly,fibronectin has been shown in vitro to mediate theadhesion of monocytes to endothelial cells [9], andcollagen I increases monocyte differentiation to macro-phages and lipid uptake by these cells [10] (Fig. 2).

A second possible pathway for a reduced amount ofcollagen in the fibrous cap is a decrease in its synthesis (Fig2). Macrophages have been demonstrated in vitro to

decrease collagen VIII synthesis, besides increasing MMP-1release, under stimulation with lipopolysaccharides andinterferon-g [11]. In accordance with this, a high variabilityin the ratio of collagen VIII and MMP-1 mRNA has beenfound in human atherosclerotic plaques [11]. Also, humanmonocytes induce a reduction in procollagen secretion byVSMC through a prostaglandin-mediated pathway [12].Oxidized low-density lipoproteins (LDL) have a dual effecton ECM regulation; at low concentration they enhance theexpression of collagen I and fibronectin by humancoronary VSMC, whereas at high concentration theyinduce apoptosis, a process that could lead to a reductionin the number of VSMC and then to a diminution in ECMsynthesis [13] (Fig. 2).

The renin-angiotensin system and extracellular matrix accumulationThe renin-angiotensin system plays a key role in theregulation of ECM. At least two distinct receptor sub-types of angiotensin II (Ang II), the major effectopeptide of the system, have been defined on the basis ofthe i r d i f fe r en t pha rm a colo gi c a nd b ioc hemi ca lproperties, and designated as Ang II type 1 (AT1) receptorand type 2 (AT2) receptor. Most of the known effects ofAng II in adult tissues are attributable to the AT1 receptor.However, recent cloning of the AT2 receptor has revealeda variety of new physiologic effects of Ang II . Thisreceptor is expressed at high levels in the developingfetus but at very low levels in the adult cardiovascularsystem. Its expression can be modulated by pathologicstates associated with tissue remodeling or inflamma-tion. In neointima formation after vascular injury, AT2receptor is re-expressed in proliferating cells and exertsan inhibitory effect on Ang II-induced mitogen signals osynthesis of ECM proteins, which results in attenuationof tissue remodeling. It may even mediate programmed

Figure 1. Putative angiotensin (Ang) II / nuclear factor kB (NF-kB) pathways in atherosclerosis. Ang II increases NF-kB activity. This may lead to extracellular matrix (ECM) accumulation via an enhanced production and through an increase in the proliferation of vascular smooth muscle cells. TFG-b1 is a major profibrogenic cytokine. Its effects on ECM may be mediated directly or through connective tissue growth factor (CTGF) systhesis. Nevertheless, CTGF could also counterbalance this effect by inducing apoptosis of vascular smooth muscle cells. On the other hand, NF-kB activation leads to recruitment of mononuclear cells that release metalloproteinases and degrade ECM. Also, NF-kB may enhance angio-tensinogen synthesis, perpetuating the increase in Ang II production. (TGF-b: transforming growth factor-b.)

108 Vascular Mechanisms

cell death, which could be considered the most extremeform of cell growth inhibition [14].

Ang II induces synthesis of ECM components byVSMC and mesangial cells in vitro [15,16•,17], probablthrough its effects on cytokines and growth factors, suchas transforming growth factor (TGF) -b1 and platelet-derived growth factor (PDGF) [16•,18]. TGF-b1 increasesthe synthesis of matrix proteins and of their receptors,such as integrins, decreases proteases, and increases theactivity of protease inhibitors [18]. Ang II enhances theproduction of TGF-b1 mRNA via AT1 receptors in ratmesangial cells [18,19] that are similar to vascular VSMC.Furthermore, Ang II is a growth factor for vascular VSM[20], which are the main source of ECM (Fig. 1). In vitro,Ang II is a bifunctional modulator of vascular VSMCgrowth, capable of inducing hypertrophy or hyperplasia[21]. It may also affect cell growth in an indirect manner,by the production of autocrine factors such as TGF-b1,platelet-derived growth factor (PDGF), and basic fibro-blast growth factor (bFGF). TGF-b1 has a pivotal role inthe cell growth response to Ang II, causing hypertrophyversus proliferation [21] and modulating the mitogenicactions of bFGF and PDGF. The mitogenic activity of AnII is increased by collagen, via PDGF AB [22], supportinthe concept of an interplay between ECM and cells. Invivo studies have shown that angiotensin-convertingenzyme (ACE) inhibition reduces vascular VSMC prolifer-ation after carotid injury in the rat [23].

Moreover, Ang II is also involved in ECM destruction.Our group has demonstrated that Ang II works as a pro-inflammatory mediator that stimulates NF-kB activity and

the expression of the chemoattractant cytokine, MCP-1 incultured monocytes and VSMC [24] (Fig. 1). In agreementwith this, the ACE inhibitor quinapril reduced NF-kB activ-ity, the expression of MCP-1 and interleukin-8 (IL-8), andthe macrophage infiltrate in a rabbit model of athero-sclerosis [24,25]. Although the amount of collagen Ipresent in the lesions was unchanged by the treatment, thiswas probably due to the short duration of the experiment,which gave no time for evidence of a possible increase incollagen deposition secondary to a reduced degradation bymacrophages. The possibility of a reduction in collagen Isynthesis secondary to a diminution in the production ofAng II seems improbable, given that collagen I gene expres-sion was not modified [25].

Recent results showing a reduction in the incidence ofacute myocardial infarctions in patients being treated withACE inhibitors [26] support these observations. Given thatplaque rupture accounts for most acute coronarysyndromes, this leads to the hypothesis that, on balance,and at least in the presence of a great inflammatory activity,the renin-angiotensin system favors ECM destruction andplaque instability. However, this hypothesis needs furtherstudy, because ACE inhibition also could work by affectingthe coagulation and fibrinolytic systems, reducing thetrend toward thrombosis.

Connective tissue growth factor and extracellular matrix regulationThis is a 38 KDa protein identified in media conditionedby human umbilical vein endothelial cells. Subsequentin vitro studies have demonstrated connective tissue

Figure 2. Recently described mechanisms that control extracellular matrix (ECM) regulation in the atherosclerotic plaque. Vascular smooth muscle cells (VSMC) are the main producers of collagen. Oxidized low-density lipoproteins (oxLDL) may enhance collagen synthesis at low concentrations or induce VSMC apoptosis at high concentrations. Fibronectin fragments play a role in monocyte adhesion to endothelial cells (EC), and collagen is involved in the differentiation of these cells into macrophages. When stimulated with lipopolysaccharide (LPS) or inter-feron-g (IFN-g), macrophages enhance collagen destruction by releasing metalloproteinases (MMPs) and decrease their own production of collagen VIII. Furthermore, they downregulate procollagen secretion by VSMC.


growth factor (CTGF) mRNA transcripts in fibroblast celllines, human VSMC, endothelial cells, and other cells. Innormal tissue, CTGF expression has been shown in thearterial vessel wall, the heart, and other organs. Enhancedregulation of CTGF has been reported in a variety offibrotic conditions, including the fibrous cap of athero-sclerotic plaques [27]. Recent data suggest that CTGF mamediate many of the profibrotic actions of TGF-b1. Bothgenes are coordinately regulated during tissue repairalthough TGF-b1-independent pathways for CTGF expres-sion have also been documented. On the other hand,overexpression of CTGF has recently been shown toinduce apoptosis of VSMC, the main producers of ECM[28]. Then, CTGF exerts effects that could lead potentiallto either an increase or a decrease in ECM (Fig. 1). Furtherstudies are needed to ascertain what is the predominantaction of CTGF in atherosclerotic plaques and what fac-tors may modulate its behavior.

Proteoglycans and plaque thrombosisIn the last few years, it has been shown that plaque throm-bosis may occur in the absence of rupture of the fibrouscap. Although the mechanism has not been completelyelucidated, an increase in the presence of proteoglycan inthe proximity of the thrombus has been observed innonruptured plaques in a series of patients with suddedeath [29]. In these areas, there were also infiltrates ofVSMC that were probably responsible for the enhanceproteoglycans synthesis. It is known that some proteogly-cans such as chondroitin sulfate, which is complexed to theheparin antagonist platelet factor-4 (PF-4), have a procoag-ulant activity, whereas others, such as heparan sulfate, havethe opposite effect. Although the proteoglycan type wasnot specifically analyzed in that report, it has beenobserved that in atherosclerosis there is enhanced produc-tion of chondroitin sulfate with no change in that ofheparan sulfate. Although further work is needed to clarifythis issue, it seems wise to speculate that, in addition tparticipating in lipid entrapment during atherogenesis,proteoglycans may have a role in some acute coronarysyndromes by favoring plaque thrombosis.

Extracellular Matrix and HypertensionHypertension induces structural changes in arteries,including an increase in collagen, destruction of elasticfibers, and VSMC hypertrophy, as well as rearrangement ofthe wall structures [30]. The accumulation of ECM in thecardiovascular system plays an important role in the devel-opment of arterial and cardiac hypertrophy, as well as inthe development of heart failure. In this sense, it has beenrecently demonstrated that aortic stiffness is an indepen-dent predictor of cardiovascular and overall mortality ipatients with end-stage renal disease [31]. The increase inECM is mediated through stretch stimuli due to theelevated pressure, and through humoral factors, the most

relevant being the renin-angiotensin system, endothelins(ET) and TGF-b1.

Renin-angiotensin systemAng II is generated in the vessel wall [32] and plays acapital role in the regulation of VSMC growth and ECMdeposition. Infusion of Ang II has been shown to increaseproliferation of medial VSMC and adventitial/interstitialfibroblasts in intramyocardial coronary arterioles of Wistarrats [33]. These effects seemed to be mediated via A 1receptors, as they were reduced by losartan. Also, Ang IImediates the increase in vascular collagen during hyper-tension through AT1 receptors. The induction of hyper-tension in mice by chronic inhibition of nitric oxidesynthesis activated the collagen I gene in the renal vascula-ture, and this effect was blocked by losartan, even in theabsence of normalization of blood pressure [34]. Ex vivo,the Ang II-induced activation of collagen I gene wasblocked by an ET receptor antagonist, suggesting that theeffect of Ang II could have been mediated, at least in part,through the stimulation of ET release [34]. Similar resultshave been obtained in vitro with mesangial cells and renaland cardiac fibroblasts [35–37]. Under stimulation withAng II, human cardiac fibroblasts showed an increase icollagen synthesis via AT1 receptors, and a decrease inMMP-1 activity [35]. Aldosterone also induced collagensynthesis, thus suggesting that in vivo Ang II could increasecollagen production in part through stimulation of therelease of this mineralocorticoid [35]. Ang II also enhancesthe expression of fibronectin, collagen I, and TGF-b1 in ratrenal fibroblasts [36] and that of fibronectin and collagenIV in rat mesangial cells [37]. In addition to Ang II, otherpeptides of the renin-angiotensin system could affect ECM.In this sense, Ang III has been shown to upregulate TGF-b1expression in mesangial cells and renal interstitial fibro-blasts, and to increase fibronectin production in fibro-blasts [38] (Fig. 3). Therefore, some of the Ang II actionsseem to be due to these degradation peptides. Thus, therelease of vasopressin requires the conversion of Ang II toAng III, and the plasminogen activator inhibitor-1 expres-sion induced by Ang II in endothelial cells is mediated byAng IV through the Ang II receptor type 4 (AT4)[39].

Several studies have demonstrated the existence oflocal generation of Ang II in various organs, includingthe vessels. During vascular injury, an activation of therenin-angiotensin system and an increase of local Ang IIgeneration have been observed in situations either asso-ciated or not with hypertension. In addition, in culturedinterstitial fibroblasts from heart and kidney, angio-tensinogen mRNA expression was upregulated inresponse to Ang II and Ang III, suggesting that thesepeptides could contribute to further increased local AngII generation through angiotensinogen gene regulation[38] (Figs. 1 and 4). The expression of this gene iscontrolled mainly by two transcription factor families,NF-kB and CCAAT/enhancer binding protein, which


bind an inducible enhancer in the angiotensinogen genepromoter [40]. Recent data have shown activation oflocal NF-kB during vascular damage, that diminished inresponse to ACE inhibition [24,25]. Moreover, in cul-tured endothelial cells and VSMC, Ang II activates NF-kBin a dose- and time-dependent manner [24]. These datsuggest that activation of NF-kB might also contribute toa sustained synthesis of local Ang II, through angio-tensinogen gene expression. Therefore, it could lead toadditional tissue damage.

In agreement with the described effects of Ang II, ACEinhibitors and AT1 blockers reduce left ventricular hyper-

trophy in patients with hypertension. In rat models, thesedrugs have been found to decrease left ventricular hyper-trophy, collagen and fibronectin in vascular walls, medialthickness, and left ventricular and myocyte hypertroph[41–45]. ACE inhibitors also reduced deposition of otherECM, such as vimentin and laminin B and the expressionof TGF-b1 [41]. Of special interest is the demonstrationthat in serum from hypertensive patients there is a reduc-tion in MMP-1 levels and an increase in those of the MMP-1 tissue inhibitor (TIMP-1) that are reversed after 1 year oftreatment with the ACE inhibitor lisinopril [46•]. More-over, in patients with left ventricular hypertrophy, there

Figure 3. Angiotensin (Ang) II and III increase transforming growth factor b1 (TGF-b1) mRNA expression, fibronectin synthesis, and c-fos mRNA expression in renal interstitial fibroblasts. A, Representative Northern blot showing an increase of TGF-b1 mRNA in response to 6-hour stimulation with 10-7 M Ang II and III. B, Ang II and III increase fibronectin expression. Cells were labelled with 35S-methionine and stimulated with 10-7 M Ang II and III, and 50 pM TGF-b1 for 24 hours. Top, The densitometric analysis of fibronectin bands represented as percentage of increase versus control in arbitrary units. Bottom, a representative autoradiograph of PAGE-SDS of fibronectin is dis-played. *—P<0.05 versus control. C, Representative blot showing induction of c-fos mRNA expression by Ang II and III. Cells were incubated with 10-7 M Ang II and III for 1 hour.

Figure 4. Angiotensin (Ang) II and III upregulate angiotensinogen gene expression in renal interstitial fibroblasts. In this reverse tran-scription polymerase chain reaction example, there is constitutive expression of angiotensinogen (Ao) mRNA, which is increased after stimulation for 6 hours with 10-7 M Ang II and Ang III. G3PDH is used as internal control.


was also a low concentration of carboxy-terminal telopep-tide of collagen type I, a product of collagen degradation,that was increased by ACE inhibition [46•]. These findingsconfirm the impact of the renin-angiotensin system onECM regulation in hypertensive human beings and suggestthe future possibility of monitoring the ECM balance itheir follow-up.

Endothelins and bradykininEndothelins are a family of vasoactive peptides that exist inthree isoforms: ET-1, ET-2, and ET-3. It has been proposedthat they play a role in hypertension, and it has beenshown that their potentiating actions on other vaso-constrictor peptides are augmented in this condition [47].Like Ang II, ET-1 regulates VSMC mitogenesis through amechanism that involves TGF-b1 synthesis. Endothelinsalso participate in ECM regulation, and they have beeshown to increase the expression of fibronectin andcollagen IV through a mechanism that involves proteinkinase C activation and TGF-b1 [15,16•,37]. In this sense,in transgenic mice made hypertensive by nitric oxideinhibition, the ET antagonist bosentan precluded theactivation of collagen I gene and the increased ECM depo-sit ion, mainly collagen I, in afferent arterioles andglomeruli without a significant effect on systolic pressure[48]. In addition, the blockade of ETA receptors reverseshypertrophy of cardiac arteries, and that of E B receptorsreduces left ventricular fibrosis in renovascular hyper-tensive rats [49]. Interestingly, ETs form a complex inter-active network with the renin-angiotensin system. Ang IIstimulates ET-1 production from endothelial cells [1••],and ET-1 increases the conversion of Ang I to Ang II incultured endothelial cells and VSMC, this effect beingblocked by ACE inhibition [16•,50]. In addition, themitogenic effects of ET-1 on VSMC and mesangial cells areblocked by losartan and quinapril [16•,37], and the Ang IIeffects on mesangial cell proliferation are blocked by theETA antagonist receptor BQ-123 [37].

Bradykinin could exert a protective role in the ECMaccumulation in hypertension. This peptide has beenshown to reduce collagen type I and III gene expression incardiac fibroblasts through the formation of arachidonicmetabolites, mainly PGI2, in rabbit cardiac fibroblasts [51].In spontaneously hypertensive rats, the bradykinin antago-nist Hoe-140 induces carotid hypertrophy [52]. Given thatACE inhibitors reduce bradykinin degradation, it would bepossible that part of their beneficial effects on collagendeposition would be mediated by bradykinin. However,the finding that quinapril reduces aortic collagen accumu-lation in rats even in the presence of Hoe-140 speaksagainst this possibility [53].

ConclusionsExtracellular matrix regulation plays an important role incardiovascular disease. Although part of the atherogenic

process, collagen deposition gives strength to the fibrouscap that recovers atherosclerotic lesions to avoid itsrupture. In the last few years, it has been shown that boththe reduction of cholesterol levels and ACE inhibition, twoeffective ways for the prevention of acute coronarysyndromes, may work through a decrease in the macro-phage infiltrate of the lesions and subsequent diminutionin collagen degradation.

On the other hand, ECM deposition in hypertensioncontributes to the development of arterial and cardiachypertrophy and heart failure. The outstanding contribu-tion of the renin-angiotensin system to ECM accumulationaccounts for a large part of the benefits of ACE inhibitorsin this condition. Nevertheless, much work remains to bedone to elucidate the complex network of interactions ofthis system with others, such as the ET system, to have themost adequate targets to control ECM accumulation.

AcknowledgmentsThe authors´ work was supported by Fondo de Investi-gación Sanitaria (96/2021), Ministerio de Educación yCiencia (PM 97/85, SAF 97/55), Comunidad Autónoma deMadrid (CAM 08.4/0003/97), EU Concerted Action Grant,BMH4-CT98-3631 (DG12-SSMI) and Instituto de Investi-gaciones Nefrológicas “Reína Sofía.”

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regulation of matrix proteins and impact on vascular structure

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