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(Hypertension. 2001;38:581.)
© 2001 American Heart Association, Inc.

Cardiovascular Biology

Vascular Remodeling in Hypertension

Roles of Apoptosis, Inflammation, and Fibrosis

Hope D. Intengan; Ernesto L. Schiffrin

Metabolic Research Unit/Diabetes Center, University of California at San Francisco (H.D.I.); and Clinical Research Institute of Montreal (E.L.S.), Montreal, Québec, Canada

Correspondence to Hope D. Intengan, PhD, Box 0540, Metabolic Research Unit/Diabetes Center, University of California at San Francisco, San Francisco, CA 94143. E-mail intengh{at}itsa.ucsf.edu

Abstract

Abstract—— Remodeling of large and small arteries contributes to the development and complications of hypertension. The focus of this review is some of the mechanisms involved in the remodeling of small arteries in hypertension. In hypertension, changes in small artery structure are basically of 2 kinds: (1) inward eutrophic remodeling, in which outer and lumen diameters are decreased, media/lumen ratio is increased, and cross-sectional area of the media is unaltered; and (2) hypertrophic remodeling, in which the media thickens to encroach on the lumen, resulting in increased media cross-sectional area and media/lumen ratio. Growth, apoptosis, inflammation, and fibrosis contribute to vascular remodeling in hypertension. Apoptosis is gene-regulated cell death, with minimal membrane disruption and inflammation, that counters cell proliferation and fine-tunes developmental growth. Apoptosis has been reported in hypertension to be both increased and decreased in different tissues, including blood vessels. Inflammation, which may be low grade, probably plays an important role in triggering fibrosis in cardiovascular disease and hypertension. Vascular fibrosis entails accumulation of collagen, fibronectin, and other extracellular matrix components in the vessel wall and is an important aspect of extracellular matrix remodeling in hypertension. Associated with this, there may be increases in cell-matrix attachment sites (integrins) and changes in their topographical localization that may modulate arterial structure. Imbalance in matrix metalloproteinase/tissue inhibitors of metalloproteinases may contribute to alteration in collagen turnover and extracellular matrix remodeling. Chronic vasoconstriction may lead to embedding of the contracted vessel structure in a remodeled extracellular matrix, contributing to the inward remodeling of the blood vessel as smooth muscle cells are rearranged around a smaller lumen. The resulting remodeling of small arteries may initially be adaptive, but eventually it becomes maladaptive and compromises organ function, contributing to cardiovascular complications of hypertension.

Key Words: arteries • apoptosis • inflammation • fibrosis • collagen • muscle, smooth

In hypertension, resistance arteries undergo eutrophic and/or hypertrophic remodeling.¹ In inward eutrophic remodeling, outer and lumen diameters are reduced, media cross-sectional area is unaltered, and media/lumen ratio is increased, without stiffening. Spontaneously hypertensive (SHR)^1,2 and 2-kidney, 1-clip Goldblatt³ rats, as well as mild essential hypertensive patients,^3,4 exhibit predominantly inward eutrophic remodeling. When media growth encroaches on the lumen to increase the media/lumen ratio, the change has been called hypertrophic remodeling. It predominates in severe hypertension, such as in deoxycorticosterone acetate (DOCA)-salt rats,⁵ 1-kidney, 1-clip (1K1C) Goldblatt rats,^6–8 Dahl salt-sensitive rats,⁹ and humans with secondary hypertension.¹⁰ Growth, apoptosis, inflammation, and fibrosis are all mechanisms that have been invoked to contribute to arterial remodeling in hypertension. Increased growth has been classically implicated in arterial remodeling in hypertension.¹¹ Chronic vasoconstriction associated with mild inflammation and activation of deposition of collagen, fibronectin, and other components of the extracellular matrix may result in a remodeled arterial structure with a smaller lumen and increased media/lumen ratio, ie, the inward eutrophic remodeled vessel. This review will center on events taking place in the media of the vessel wall during vascular remodeling. Although the endothelium may participate in some of these effects to an important degree, its contribution will only be addressed peripherally, and the reader is directed to the many reviews on the subject.

Apoptosis

The finding that inward eutrophic remodeling may be predominant in some forms of hypertension has raised the possibility that growth may be compensated or modified by countervailing mechanisms in hypertension, particularly apoptosis. Apoptosis is gene-regulated cell death, first recognized in development as a mechanism involved in the fine-tuning of growth.¹² Apoptosis is also invoked in cancer, immune diseases, Parkinson’s disease, and Alzheimer’s dementia and has been reported to different degrees in atherosclerosis, restenosis, myocardial infarction, and heart failure. Apoptosis is increased in hypertensive rat heart,^13–16 brain,¹³ kidney,^13,17 and arteries, where smooth muscle cell (SMC) death modulates remodeling.^18,19 Aortae of DOCA-salt rats,²⁰ SHR,²¹ and angiotensin-infused rats²² exhibit apoptosis detectable by DNA laddering, augmented in situ end-labeling of fragmented DNA, and/or Bax/Bcl-2 ratio. Vascular SMC cells in hypertensive rats are more prone to apoptosis, as shown by serum deprivation of aortic SMC from stroke-prone SHR (SHR-sp).²³ In SHR, by 8 and 12 weeks but not 4 weeks of age, blood pressure, small artery media/lumen ratio, and apoptosis were increased.²⁴ Enhanced apoptosis in resistance arteries may be bed specific. In SHR small intramyocardial arteries, the Bax/Bcl-2 ratio was reduced, suggesting decreased apoptosis,²⁵ whereas arterioles and capillaries were more prone to apoptosis, suggesting that in these beds, apoptosis influences vascular resistance via rarefaction, as in 1K1C Goldblatt hypertensive rats.²⁶

The role of apoptosis in vascular remodeling remains unclear. In inward eutrophic remodeling, a combination of growth and apoptosis, with apoptosis localized to the outer periphery, reduces the outer diameter of the vessel, whereas inward growth decreases lumen diameter, which may explain the maintenance of media volume.²⁷ Whether apoptosis is a growth-related compensatory mechanism or a primary process remains to be clarified. Interestingly, there are reports of reduced SMC apoptosis in the small arteries of young SHR, suggesting that a decrease in the apoptotic rate in resistance blood vessels contributes to their enhanced growth in this model.²⁸ Apoptosis modulators in the vasculature are numerous and complex. Candidates may include reactive oxygen species,²⁹ NO,³⁰ angiotensin type 2 (AT₂) receptors,³¹ and the endothelin system.³² Reactive oxygen species are involved in the pathogenesis of hypertension and in apoptosis of vascular cells, where, specifically, O₂^- induces proliferation and H₂O₂ may induce apoptosis via a protein kinase C–dependent mechanism.³³ Angiotensin (Ang) II is also a potential trigger of apoptosis.^31,34 Ang II infusion in normotensive rats raised blood pressure and increased apoptotic rate in thoracic aortae by activation of angiotensin type 1 (AT₁) and AT₂ receptor subtypes.²² Indeed, following AT₁ receptor blockade in SHR, vascular SMC apoptosis increased, an effect attenuated by AT₂ receptor antagonism.³⁴ In rat aortic SMC, cyclic stretch increased endothelin B (ET_B) receptor mRNA and promoted ligand occupancy of the resultant receptors by reducing endothelin A (ET_A) receptor mRNA. Exogenous endothelin induced apoptosis via ET_B receptors.³² On the other hand, there is evidence for a survival and anti-apoptotic effect mediated by endothelin A (ET_A) receptors.¹⁹

Apoptosis, Vascular Remodeling, and Results of Therapy

Vascular remodeling contributes to end-organ damage in hypertension, providing a rationale for regression of remodeling of blood vessels as a therapeutic aim. Large conductance Ca²⁺ channel blockers stimulate SMC apoptosis, as shown by studies with nifedipine³⁵ and amlodipine²¹ on SHR thoracic aorta SMCs and with verapamil on rat coronary artery SMCs.³⁶ During early treatment, ACE inhibition, AT₁ receptor antagonism, and Ca²⁺ channel blockade stimulated medial SMC apoptosis in thoracic aortae of SHR, although mere blood pressure lowering by hydralazine had no effect.³⁷ Some studies suggested that apoptosis occurs in waves for limited periods.^19,34,37 In other studies, increased apoptotic rate persisted through 12 weeks of treatment with enalapril and amlodopine²¹ and through 16 weeks with quinapril.³⁸ Increased apoptosis also occurs in aortae of DOCA-salt rats, and treatment with ET_A-selective endothelin receptor antagonists enhances apoptosis in this model.¹⁹ Antihypertensive therapy may therefore contribute to regression of vascular wall growth via activation of pro-apoptotic mechanisms.

Inflammation

The actions of Ang II are mediated in large measure by stimulation of production of superoxide anion and activation of redox-sensitive genes.³⁹ Some of these include genes participating in inflammatory responses to angiotensin stimulation.^40–42 Among these are nuclear factor B and AP-1, associated with upregulation of adhesion molecules such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, and stimulation of the production of chemokines such as monocyte chemotactic protein 1 followed by recruitment of monocytes/macrophages to the vascular wall. In rats doubly transgenic for human renin and human angiotensinogen, which develop a malignant form of hypertension, inflammatory mediators were shown to be activated, with upregulation of adhesion molecules in the kidney and infiltration by monocyte-macrophages.⁴³ Although the latter processes and the role of Ang II in triggering them have been clearly identified in the heart and kidney⁴³ and play a role in the progression of atherosclerosis in large conduit vessels,⁴⁴ their participation in small artery remodeling is only now starting to be investigated. However, we have often noted that in small arteries, increased numbers of inflammatory cells may be observed in hypertension in the adventitia, an often neglected layer of the vascular wall. Indeed, the adventitia has recently been identified as an important source of oxygen free radicals potentially participating in vascular pathophysiology.⁴⁵ It is likely that inflammation and the increased oxidative stress, which probably act as an important trigger and may to a large extent be Ang II–dependent, play a role in the process leading to remodeling of small and large vessels in hypertension.⁴⁶ Nonetheless, this remains to be further investigated. As well, the potential importance of inflammation in the vascular wall from a therapeutic viewpoint remains an interesting but largely unexplored area of potential application of the new knowledge of participation of inflammatory mediators in remodeling of the vasculature.

Vascular Fibrosis

Fibrillar extracellular matrix in the vessel wall includes structural proteins (collagen and elastin) and adhesive proteins (eg, laminin and fibronectin). In hypertension, vascular fibrosis entails in large part, the deposition of extracellular matrix, particularly collagen, in the arterial wall. In normal arteries, fibrillar collagens I and III are major constituents of the intima, media, and adventitia, whereas types I, III, IV, and V are in endothelial and SMC basement membranes.⁵⁸ There are early reports^47,48 of increased collagen synthesis in the arterial wall in hypertension that occurred globally in SHR and DOCA-salt rat aortae, mesenteric arteries, cerebral microvessels, pial arteries, and basilar arteries. Collagen accumulation may not follow synthesis and may be bed specific, as it occurs in coronary arteries⁴⁹ but less consistently in aortae of SHR⁵⁰ or DOCA-salt rats,⁵¹ although recent studies report increases in collagen III but not collagen I in Japanese and Lyon SHR strains.⁵² In SHR-sp aortae, total collagen is not augmented.⁵³ Nonetheless, upregulated gene expression of types I, III, and IV was detected in aortae and mesenteric arteries.⁵⁴ Collagen was reported increased in mesenteric small arteries of SHR^55,56 or subcutaneous resistance arteries from essential hypertensive humans.⁵⁷ Collagen is the extracellular fibrillar component that may alter the passive pressure/diameter relation of arteries at higher pressures and induce a progressive stiffening of the vascular wall. However, we showed in small arteries from these relatively young humans with mild to moderate hypertension that increased collagen deposition may be associated with reduced stiffness.⁵⁷ This indicates that it is not the amount of collagen in the wall but rather the recruitment of collagen fibers at higher pressures that results in increased stiffness of the vessel wall. Early in hypertension, both in experimental animals and in humans, the vessel wall components may be less stiff in spite of increased collagen deposition, but as hypertension progresses, other changes, particularly in extracellular matrix–SMC anchoring, may result in normalization of wall stiffness.⁵⁸ Later, the increased stiffness that occurs in advanced hypertension may develop.⁵⁹ Fibronectin also accumulated in DOCA-salt,⁶⁰ SHR,⁶¹ Dahl salt-sensitive,⁶² SHR-sp,⁶³ and Ang II–infused rat aortae,⁶⁴ probably independently of blood pressure. In many of these models, stimulation of AT₁ receptors is the likely mechanism. However, the extent to which fibronectin accumulates in resistance arteries in hypertension is presently unclear, although we have preliminary evidence (Q. Pu and E.L. Schiffrin, unpublished, 2001) using confocal microscopy that demonstrated increased fibronectin in the media of resistance arteries of SHR-sp.

Ang II stimulates human vascular SMC production of collagen I,⁶⁵ activating the procollagen type I gene via the mitogen-activated protein kinase/ERK pathway.⁶⁶ These effects are mediated, at least in part, by AT₁ receptors.^62,64,65 AT₂ receptors may also play a role^67,68 via G_I proteins.⁶⁹ Involvement of angiotensin evokes the possible involvement of multiple autocrine growth factors that modulate the responses to angiotensin, such as transforming growth factor–ß (TGF-ß) and platelet-derived growth factor,⁷⁰ as well as other growth factors, including insulin-like growth factor and basic fibroblast growth factor. Ang II increased TGF-ß in a losartan-sensitive manner, and in human arterial SMC, angiotensin-stimulated collagen synthesis was inhibited by blocking TGF-ß.⁷¹ A relationship between Ang II and TGF-ß was suggested previously, in which stretch was the experimental stimulus of collagen synthesis in rabbit aortic SMC.⁷² Stretch concomitantly increased immunoreactive Ang II and TGF-ß in the culture medium, and elicited collagen synthesis. Angiotensin antagonism attenuated TGF-ß secretion and collagen synthesis. Collagen synthesis was inhibited by TGF-ß neutralizing antibody or truncated TGF-ß type II receptor, suggesting a linear pathway where Ang stimulates TGF-ß secretion, which in turn triggers collagen synthesis. Indeed, exogenous TGF-ß in aortic SMC results in collagen synthesis,⁷² and in human cells, a role of TGF-ß in stretch-induced collagen synthesis was also detected.⁷³ However, in SHR SMC these effects of TGF-ß were blunted versus WKY.⁷⁴

Other modulators of collagen synthesis include aldosterone and endothelin. Aortic collagen accumulation was attenuated by inhibiting ACE²¹ or by antagonizing aldosterone.⁷⁵ Collagen I synthesis is stimulated by endothelin-1 (ET-1) in coronary artery SMC.⁷⁶ Indeed, in the N-nitro-L-arginine methyl ester (L-NAME) model of hypertension, ET-1 synthesis is increased in renal microvessels and activates local collagen formation.⁷⁷ Losartan blocked L-NAME–induced fibrosis, and stimulatory effects of angiotensin on collagen I-² chain promoter activity were attenuated by endothelin receptor antagonism.⁷⁸ In DOCA-salt hypertensive rats, which have very significant cardiac fibrosis, administration of an ET_A receptor antagonist ameliorated interstitial and perivascular fibrosis.⁷⁹ In aldosterone-infused rats, vascular changes were prevented by endothelin antagonism,⁸⁰ and collagen deposition in heart and arteries was also demonstrated to be endothelin dependent.⁸¹ Cardiovascular fibrosis is, in large part, a humoral-determined event, with central roles of Ang II, ET-1, and mineralocorticoids.

Matrix metalloproteinase (MMP) activity may modulate hypertension-related accumulation of extracellular matrix proteins in resistance arteries. MMPs are Zn²⁺- and Ca²⁺-dependent proteolytic enzymes that degrade extracellular matrix proteins.^82,83 Several different MMPs are present in the vasculature. These include collagenases (eg, interstitial collagenase MMP-1 and MMP-13) that digest structural or fibrillar collagens (types I to III). Gelatinases A (MMP-2) and B (MMP-9), which digest denatured collagen (gelatin) and collagen types IV and V, are found in the subendothelial basement membrane. Stromelysins (eg, MMP-3) are also found. They digest adhesive molecules such as laminin, fibronectin, nonfibrillar collagens, and proteoglycans. Finally, there are the membrane-type MMPs (MT1-MMP or MMP-14). MT1-MMP activates other MMPs.⁸⁴ MT1-MMP and MMP-2 act as an integral part of multiprotein enzymatic complex. MT1-MMP may activate latent MMP-13, which in turn activates MMP-9. MT1-MMP may form a ternary complex with tissue inhibitors of metalloproteinase (TIMP)-2 and pro-MMP-2 that depends on the tethering of pro-MMP-2 by _vß3-integrin. Indeed, a number of integrins, including _5ß1, may be involved in activation of MMPs. MMP-mediated modulation of extracellular matrix could result via integrin-mediated signaling in cytoskeletal reorganization. This could contribute to both differential restructuring of extracellular matrix proteins and reorganization of SMCs in the vascular wall in hypertension. In serum from SHR with extensive myocardial fibrosis^85,86 and in humans with essential hypertension,⁸⁷ markers of enhanced synthesis of type I collagen are not balanced by markers of increased type I collagen degradation. In hypertensive patients in whom type I collagen precursors were augmented, serum concentrations of MMP-1 were in fact reduced.⁸⁸ MMP-1 activity was decreased in the mesenteric arterial bed of young SHR before hypertension was established.⁸⁹ MMP-3 activity was also decreased, which may promote accumulation of fibronectin and proteoglycans in SHR.^90,91 Pro-MMP2 and activated MMP-2 activities were diminished in mesenteric arteries from adult SHR,⁸⁹ which could facilitate accumulation of types IV and V collagen and fibronectin.⁵⁴ Changes in MMP activity may thus contribute to resistance artery remodeling in hypertension by modulating extracellular matrix profile and interacting with adhesion receptors. Significant decreases in MMP activity in young SHR-sp vessels could result in decreased collagen turnover and increased collagen accumulation, whereas in the older hypertensive rats, vascular increased MMP activity suggests countervailing activation of MMPs or inhibition of activity of TIMPs to reduce collagen accumulation in the vascular wall.

We have proposed that remodeling of the small arteries occurring in both humans and experimental models of hypertension implies a remodeling of the extracellular matrix and of extracellular–vascular SMC attachment sites and a restructuring of vascular SMCs that may in part be triggered by the adhesion molecules that mediate anchoring to ECM components. These adhesion molecules (integrins) transduce signals from the extracellular to the cytoskeletal fibrillar components.²⁷ Because of changes in extracellular matrix components and corresponding adhesion receptors, interactions between SMCs and matrix proteins shift, quantitatively and/or topographically, resulting in a rearrangement of SMCs and a restructured vascular wall. We hypothesized that vascular remodeling may involve changes in these attachment sites. We have shown that expression of integrins is abnormal in SHR blood vessels and is modulated by age.⁵⁵ Mesenteric arteries from SHR exhibited an increase in expression of _vß₃- and ₅ß₁-integrins from 6 to 20 weeks. In arteries from adult SHR, the volume density of collagen was significantly increased.⁵⁵ Bézie et al⁵⁰ have also reported increases in ₅-integrins and fibronectin, their main ligand, in aorta from SHR. Such changes may represent an increase in cell–extracellular matrix attachment sites and perhaps also their topographical localization that may modulate arterial structure. One may envision that in the hypertensive state, progressive deposition of extracellular matrix fibrillar components anchored to SMCs of the chronically constricted vessel may result in an artery with a persistently smaller lumen, as found in the inward eutrophic remodeling characteristic of small arteries of SHR and in essential hypertension. In addition, changes in the attachment of the fibrillar elements of the matrix may occur that contribute to arterial inward remodeling by altering the anchoring of SMC to fibrillar components of the extracellular matrix. This would also alter signal transduction by integrins from outside the cell to the SMC cytoskeleton, promoting restructuring of the SMC in the vessel wall.

Growth of the smooth muscle in the media of blood vessels may be facilitated by several extracellular matrix proteins. Tenascin-C, an extracellular matrix glycoprotein and ligand for _vß₃, is one such extracellular component that may be important in vascular remodeling in hypertension. It co-localizes with proliferating SMCs in SHR⁹² and may be a survival factor that promotes proliferation and protects SMCs from apoptosis. Fibronectin matrix assembly may likewise facilitate vascular SMC growth. As mentioned previously, total fibronectin⁵⁰ and ₅ß1-integrins^50,55 are increased in arteries of SHR. This suggests that fibronectin matrix assembly, which requires the interaction between the arginine-glycine-aspartate site of fibronectin and ₅ß₁-integrins,⁹³ is also elevated in SHR vessels. Another arginine-glycine-aspartate–containing protein that may be associated with proliferation is osteopontin, a secreted glycoprotein adhesive for vascular SMCs via _vß₃-integrins.⁹⁴ In vitro studies have demonstrated that osteopontin overexpression is associated with arterial SMC proliferation.⁹⁵

Fibrosis, Vascular Remodeling, and Therapy

Arterial wall thickening may increase peripheral resistance and blood pressure, in part by physically encroaching on the lumen and, where collagen is invoked, by increasing wall stiffness to reduce lumen diameter at a given pressure.²⁷ In SHR resistance arteries, collagen density or relative content was normalized by ACE inhibition,^55,56 AT₁ receptor blockade,⁵⁵ and the dihydropyridine Ca²⁺-channel blocker amlodipine.⁵⁶ Aldosterone antagonism also reduced collagen in SHR aortae.⁹⁶ Likewise, in vessels from SHR-sp and DOCA-salt rats, AT₁ receptor antagonism reduced collagen types I, III, and IV mRNA.^63,97 At least in SHR, amelioration of collagen accumulation is not due to blood pressure lowering per se, as minoxidil had no effect on collagen content in aortae or in renal and superior mesenteric arteries.⁹⁸ Thus, regression of vascular fibrosis may occur independently of blood pressure lowering.

Conclusion

In hypertension, vascular remodeling contributes to increased peripheral resistance, impacting both development and complications of hypertension. Although growth is the mechanism that is more classically associated with vascular remodeling, it has increasingly been appreciated that apoptosis, low-grade inflammation, and vascular fibrosis are dynamic processes that also may influence the degree of remodeling that occurs (summarized in the Figure). Inward growth may be associated with peripheral apoptosis, contributing to eutrophic remodeling. Low-grade inflammation, perhaps angiotensin- or endothelin-dependent and triggered in part by increased oxidative stress in the vascular wall stimulated by these peptides or other agents, may elicit growth factor–mediated extracellular matrix remodeling. Changes in the anchoring of cells to extracellular fibrillar components may alter cell attachment, changing the architecture of the vessel wall, and may promote abnormal intracellular transduction of extracellular input to the cytoskeleton of SMC, contributing to SMC cell restructuring. Chronic vasoconstriction may result in an inwardly remodeled blood vessel as the contracted vessel structure becomes embedded in a remodeled extracellular matrix, further promoting re-arrangement of SMCs around a smaller lumen. Growth, apoptosis, inflammation, and fibrosis of blood vessels may thus all contribute to vascular remodeling. The resulting arterial remodeling may initially be adaptive but eventually becomes maladaptive and compromises organ function, contributing to cardiovascular complications of hypertension. Accordingly, growth, apoptosis, inflammation, and fibrosis all are important end points and attractive therapeutic objectives in hypertensive vascular disease.

View larger version (47K): [in this window] [in a new window]   Proposed model of the pathophysiologic mechanisms leading to small artery remodeling in hypertension. Blood pressure (BP) may rise progressively as a result of genetically and/or environmentally determined increased neurohumoral/hormonal (endocrine, paracrine, or autocrine) drive. Either directly or indirectly via the action of vasoactive peptides such as Ang II and ET-1, mediated in part by increased oxidative stress, vasoconstriction is induced and SMC growth and apoptosis, low-grade inflammation, and vascular fibrosis occur, leading to vascular remodeling. Vascular remodeling may feed back by amplifying BP elevation. SMC growth and apoptosis, low-grade inflammation, and vascular fibrosis are dynamic processes that influence vessel remodeling. Inward growth associated with peripheral apoptosis may lead to eutrophic remodeling. Low-grade inflammation, perhaps triggered by Ang II or ET-1 stimulation of oxidative stress in the vascular wall, may promote growth factor–mediated extracellular matrix remodeling. Changes in the anchoring of cells to extracellular fibrillar components may alter extracellular-SMC attachments (integrins), changing the architecture of the vessel wall, and the intracellular transduction of extracellular signals to the SMC cytoskeleton, favoring restructuring of SMC cells. Changes in MMP/TIMPs may contribute to alteration in collagen turnover and promote extracellular matrix remodeling. Chronic vasoconstriction may lead to embedding of the contracted vessel structure in a remodeled extracellular matrix, contributing to the inward remodeling of the blood vessel as SMCs become rearranged around a smaller lumen. Growth, apoptosis, inflammation, and fibrosis in the blood vessel wall may thus all contribute to vascular remodeling. Although not developed in the text, endothelial dysfunction, in part induced by BP elevation and mediated by reduced NO bioavailability as NO is scavenged by oxygen free radicals, also promotes remodeling. NO would under normal conditions inhibit vasoconstriction, growth, and collagen deposition and promote apoptosis. Remodeling may initially be adaptive but eventually becomes maladaptive and compromises organ function, contributing to cardiovascular complications of hypertension.

Acknowledgments

The authors’ work was supported by grants 13570 and 37917 and a group grant to the Multidisciplinary Research Group on Hypertension to E.L.S., all from the Canadian Institutes of Health Research (CIHR, previously Medical Research Council of Canada). H.D.I. was supported by a Centennial Fellowship (now entitled Senior Research Fellowship) from CIHR.

Received March 27, 2001; first decision June 5, 2001; accepted July 18, 2001.

References

1. Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, Heistad DD. Vascular remodeling. Hypertension. . 1996; 28: 505–506.
2. Deng LY, Schiffrin EL. Effects of endothelin-1 and vasopressin on resistance arteries of spontaneously hypertensive rats. Am J Hypertens. . 1992; 5: 817–822.[Medline] [Order article via Infotrieve]
3. Li JS, Knafo L, Turgeon A, Garcia R, Schiffrin EL. Effect of endothelin antagonism on blood pressure and vascular structure in renovascular hypertensive rats. Am J Physiol. . 1996; 40: H88–H93.
4. Korsgaard N, Aalkjær C, Heagerty AM, Izzard AS, Mulvany MJ. Histology of subcutaneous small arteries from patients with essential hypertension. Hypertension. . 1993; 22: 523–526.[Abstract/Free Full Text]
5. Schiffrin EL, Deng LY, Larochelle P. Morphology of resistance arteries and comparison of effects of vasoconstrictors in mild essential hypertensive patients. Clin Invest Med. . 1993; 16: 177–186.[Medline] [Order article via Infotrieve]
6. Deng LY, Schiffrin EL. Effects of endothelin on resistance arteries of DOCA-salt hypertensive rats. Am J Physiol. . 1992; 262: H1782–H1787.[Abstract/Free Full Text]
7. Korsgaard N, Mulvany MJ. Cellular hypertrophy in mesenteric resistance vessels from renal hypertensive rats. Hypertension. . 1998; 12: 162–167.[Abstract/Free Full Text]
8. Deng LY, Schiffrin EL. Morphologic and functional alterations of mesenteric small resistance arteries in early renal hypertension in the rat. Am J Physiol. . 1991; 261: H1171–H1177.[Abstract/Free Full Text]
9. D’Uscio LV, Barton M, Shaw S, Moreau P, Luscher TF. Structure and function of small arteries in salt-induced hypertension: effects of chronic endothelin-subtype-A-receptor blockade. Hypertension. . 1997; 30: 905–911.[Abstract/Free Full Text]
10. Rizzoni D, Porteri E, Castellano M, Bettoni G, Muiesan ML, Muissan P, Gaulini SM, Agabiti-Rosei E. Vascular hypertrophy and remodeling in secondary hypertension. Hypertension. . 1996; 28: 785–790.[Abstract/Free Full Text]
11. Lee RMKW, Owens GK, Scott-Burden T, Head RJ, Mulvany MJ, Schiffrin EL. Pathophysiology of smooth muscle in hypertension. Can J Physiol Pharmacol. . 1995; 73: 574–584.[Medline] [Order article via Infotrieve]
12. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. . 1995; 267: 1456–1462.[Abstract/Free Full Text]
13. Hamet P, Richard L, Dam TV, Teiger E, Orlov SN, Gaboury L, Gossard F, Tremblay J. Apoptosis in target organs of hypertension. Hypertension. . 1995; 26: 642–648.[Abstract/Free Full Text]
14. Diez J, Panizo A, Hernandez M, Vega F, Sola I, Fortuno MA, Pardo J. Cardiomyocyte apoptosis and cardiac angiotensin-converting enzyme in spontaneously hypertensive rats. Hypertension. . 1997; 30: 1029–1034.[Abstract/Free Full Text]
15. Fortuno MA, Ravassa S, Etayo JC, Diez J. Overexpression of Bax protein and enhanced apoptosis in the left ventricle of spontaneously hypertensive rats: effects of AT₁ blockade with losartan. Hypertension. . 1998; 32: 280–286.[Abstract/Free Full Text]
16. Liu JJ, Peng L, Bradley CJ, Zulli A, Shen J, Buxton BF. Increased apoptosis in the heart of genetic hypertension, associated with increased fibroblasts. Cardiovasc Res. . 2000; 45: 729–735.[Abstract/Free Full Text]
17. Rodriguez-Lopez AM, Flores O, Arevalo MA, Lopez-Novoa JM. Glomerular cell proliferation and apoptosis in uninephrectomized spontaneously hypertensive rats. Kidney Int Suppl. . 1998; 68: S36–S40.[Medline] [Order article via Infotrieve]
18. Cho A, Cantman DW, Langille BL. Apoptosis (programmed cell death) in arteries of the neonatal lamb. Circ Res. . 1995; 76: 168–175.[Abstract/Free Full Text]
19. Hamet P, deBlois D, Dam TV, Richard L, Teiger E, Tea BS, Orlov SN, Tremblay J. Apoptosis and vascular wall remodeling in hypertension. Can J Physiol Pharmacol. . 1996; 74: 850–861.[Medline] [Order article via Infotrieve]
20. Sharifi AM, Schiffrin EL. Apoptosis in aorta of deoxycorticosterone acetate–salt hypertensive rats: effect of endothelin receptor antagonism. J Hypertens. . 1997; 15: 1441–1448.[Medline] [Order article via Infotrieve]
21. Sharifi AM, Schiffrin EL. Apoptosis in vasculature of spontaneously hypertensive rats: effect of an angiotensin-converting enzyme inhibitor and a calcium channel antagonist. Am J Hypertens. . 1998; 11: 1108–1116.[Medline] [Order article via Infotrieve]
22. Diep QN, Li JS, Schiffrin EL. In vivo study of AT₁ and AT₂ angiotensin receptors in apoptosis of rat blood vessels. Hypertension. . 1999; 34: 617–624.[Abstract/Free Full Text]
23. Devlin AM, Clark JS, Reid JL, Dominiczak AF. DNA synthesis and apoptosis in smooth muscle cells from a model of genetic hypertension. Hypertension. . 2000; 36: 110–115.[Abstract/Free Full Text]
24. Rizzoni D, Rodella L, Porteri E, Rezzani R, Guelfi D, Piccoli A, Castellano M, Muiesan ML, Bianchi R, Rosei EA. Time course of apoptosis in small resistance arteries of spontaneously hypertensive rats. J Hypertens. . 2000; 18: 885–891.[Medline] [Order article via Infotrieve]
25. Vega F, Panizo A, Pardo-Mindan J, Diez J. Susceptibility to apoptosis measured by MYC, BCL-2, and BAX expression in arterioles and capillaries of adult spontaneously hypertensive rats. Am J Hypertens. . 1999; 12: 815–820.[Medline] [Order article via Infotrieve]
26. Gobe G, Browning J, Howard T, Hogg N, Winterford C, Cross R. Apoptosis occurs in endothelial cells during hypertension-induced microvascular rarefaction. J Struct Biol. . 1997; 118: 63–72.[Medline] [Order article via Infotrieve]
27. Intengan HD, Schiffrin EL. Structure and mechanical properties of resistance arteries in hypertension: role of adhesion molecules and extracellular matrix determinants. Hypertension. . 2000; 36: 312–318.[Abstract/Free Full Text]
28. Dickhout JG, Lee RMKW. Apoptosis in the muscular arteries from young spontaneously hypertensive rats. J Hypertens. . 1999; 17: 1413–1419.[Medline] [Order article via Infotrieve]
29. Irani K. Oxidant signaling in vascular cell growth, death, and survival: a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circ Res. . 2000; 87: 179–183.[Abstract/Free Full Text]
30. Pollman MJ, Yamada T, Horiuchi M, Gibbons GH. Vasoactive substances regulate vascular smooth muscle cell apoptosis: countervailing influences of nitric oxide and angiotensin II. Circ Res. . 1996; 79: 748–756.[Abstract/Free Full Text]
31. Yamada T, Horiuchi M, Dzau VJ. Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci U S A. . 1996; 93: 156–160.[Abstract/Free Full Text]
32. Cattaruzza M, Dimigen C, Ehrenreich H, Hecker M. Stretch-induced endothelin B receptor–mediated apoptosis in vascular smooth muscle cells. FASEB J. . 2000; 14: 991–998.[Abstract/Free Full Text]
33. Li PF, Maasch C, Haller H, Dietz R, von Harsdorf R. Requirement for protein kinase C in reactive oxygen species–induced apoptosis of vascular smooth muscle cells. Circulation. . 1999; 100: 967–973.[Abstract/Free Full Text]
34. Tea BS, Der Sarkissian S, Touyz RM, Hamet P, deBlois D. Proapoptotic and growth-inhibitory role of angiotensin II type 2 receptor in vascular smooth muscle cells of spontaneously hypertensive rats in vivo. Hypertension. . 2000; 35: 1069–1073.[Abstract/Free Full Text]
35. Stead S, Werstiuk ES, Lee RM. Nifedipine induces apoptosis in cultured vascular smooth muscle cells from spontaneously hypertensive rats. Life Sci. . 2000; 67: 895–906.[Medline] [Order article via Infotrieve]
36. Leszczynski D, Zhao Y, Luokkamaki M, Foegh ML. Apoptosis of vascular smooth muscle cells: protein kinase C and oncoprotein Bcl-2 are involved in regulation of apoptosis in non-transformed rat vascular smooth muscle cells. Am J Pathol. . 1994; 145: 1265–1270.[Abstract]
37. deBlois D, Tea BS, Than VD, Tremblay J, Hamet P. Smooth muscle apoptosis during vascular regression in spontaneously hypertensive rats. Hypertension. . 1997; 29: 340–349.[Abstract/Free Full Text]
38. Diez J, Panizo A, Hernandez M, Pardo J. Is the regulation of apoptosis altered in smooth muscle cells of adult spontaneously hypertensive rats? Hypertension. . 1997; 29: 776–780.[Abstract/Free Full Text]
39. Griendling KK, Ushio-Fukai M. Reactive oxygen species as mediators of angiotensin II signaling. Reg Peptides. . 2000; 91: 21–27.[Medline] [Order article via Infotrieve]
40. Kranzhöfer R, Schmidt J, Pfeiffer CAH, Hagl S, Libby P, Kübler W. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. . 1999; 19: 1623–1629.[Abstract/Free Full Text]
41. Ruiz-Ortega M, Lorenzo O, Rupérez M, König S, Wittig B, Egido J. Angiotensin II activates nuclear transcription factor B through AT₁ and AT₂ in vascular smooth muscle cells - Molecular mechanisms. Circ Res. . 2000; 86: 1266–1272.[Abstract/Free Full Text]
42. Muller DN, Dechend R, Mervaala EMA, Park JK, Schmidt F, Fiebeler A, Theuer J, Breu V, Ganten D, Haller H, Luft FC. NF-B inhibition ameliorates angiotensin II–induced inflammatory damage in rats. Hypertension. . 2000; 35: 193–201.[Abstract/Free Full Text]
43. Luft FC, Mervaala E, Müller DN, Gross V, Schmidt F, Park JK, Schmitz C, Lippoldt A, Breu V, Dechend R, Dragun D, Schneider W, Ganten D, Haller H. Hypertension-induced end-organ damage: a new transgenic approach to an old problem. Hypertension. . 1999; 33: 212–218.[Abstract/Free Full Text]
44. Weiss D, Kools JJ, Taylor WR. Angiotensin-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice. Circulation. . 2001; 103: 448–454.[Abstract/Free Full Text]
45. Pagano PJ, Clark JK, Cifuentes-Pagano ME, Clark SM, Callis GM, Quinn MT. Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: Enhancement by angiotensin II. Proc Natl Acad Sci U S A. . 1997; 94: 14483–14488.[Abstract/Free Full Text]
46. Shekhonin BV, Domogatsky SP, Muzykantov VR, Idelson GL, Rukosuev VS. Distribution of type I, III, IV, and V collagen in normal and atherosclerotic human arterial wall: immunomorphological characteristics. Coll Relat Res. . 1985; 5: 355–368.[Medline] [Order article via Infotrieve]
47. Ooshima A, Fuller GC, Cardinale GJ, Spector S, Udenfriend S. Increased collagen synthesis in blood vessels of hypertensive rats and its reversal by antihypertensive agents. Proc Natl Acad Sci U S A. . 1974; 71: 3019–3023.[Abstract/Free Full Text]
48. Ooshima A, Fuller G, Cardinale G, Spector S, Udenfriend S. Collagen biosynthesis in blood vessels of brain and other tissues of the hypertensive rat. Science. . 1975; 190: 898–900.[Free Full Text]
49. Anversa P, Melissari M, Tardini A, Olivetti G. Connective tissue accumulation in the left coronary artery of young SHR. Hypertension. . 1984; 6: 526–529.[Abstract/Free Full Text]
50. Bézie Y, Lamaziere JM, Laurent S, Challande P, Cunha RS, Bonnet J, Lacolley P. Fibronectin expression and aortic wall elastic modulus in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. . 1998; 18: 1027–1034.[Abstract/Free Full Text]
51. Karam H, Heudes D, Gonzales MF, Loffler BM, Clozel M, Clozel JP. Respective role of humoral factors and blood pressure in aortic remodeling of DOCA hypertensive rats. Am J Hypertens. . 1996; 9: 991–998.[Medline] [Order article via Infotrieve]
52. Chamiot Clerc P, Renaud JF, Blacher J, Legrand M, Samuel JL, Levy BI, Sassard J, Safar ME. Collagen I and III and mechanical properties of conduit arteries in rats with genetic hypertension. J Vasc Res. . 1999; 36: 139–146.[Medline] [Order article via Infotrieve]
53. Mizutani K, Ikeda K, Kawai Y, Yamori Y. Biomechanical properties and chemical composition of the aorta in genetic hypertensive rats. J Hypertens. . 1999; 17: 481–487.[Medline] [Order article via Infotrieve]
54. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Ishimura Y, Chatani F, Iwao H. Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-ß1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther. . 1995; 273: 509–515.[Abstract/Free Full Text]
55. Intengan HD, Thibault G, Li JS, Schiffrin EL. Resistance artery mechanics, structure, and extracellular components in spontaneously hypertensive rats: effects of angiotensin receptor antagonism and converting enzyme inhibition. Circulation. . 1999; 100: 2267–2275.[Abstract/Free Full Text]
56. Sharifi AM, Li JS, Endemann D, Schiffrin EL. Effects of enalapril and amlodipine on small-artery structure and composition, and on endothelial dysfunction in spontaneously hypertensive rats. J Hypertens. . 1998; 16: 457–466.[Medline] [Order article via Infotrieve]
57. Intengan HD, Deng LY, Li JS, Schiffrin EL. Mechanics and composition of human subcutaneous resistance arteries in essential hypertension. Hypertension. . 1999; 33: 569–574.[Abstract/Free Full Text]
58. Thybo NK, Mulvany MJ, Jastrup B, Nielsen H, Aalkjaer C. Some pharmacological and elastic characteristics of isolated subcutaneous small arteries from patients with essential hypertension. J Hypertens. . 1996; 14: 993–998.[Medline] [Order article via Infotrieve]
59. Mulvany MJ. A reduced elastic modulus of vascular wall components in hypertension. Hypertension. . 1992; 20: 7–9.[Free Full Text]
60. Takasaki I, Chobanian AV, Sarzani R, Brecher P. Effect of hypertension on fibronectin expression in the rat aorta. J Biol Chem. . 1990; 265: 21935–21939.[Abstract/Free Full Text]
61. Saouaf R, Takasaki I, Eastman E, Chobanian AV, Brecher P. Fibronectin biosynthesis in the rat aorta in vitro: changes due to experimental hypertension. J Clin Invest. . 1991; 88: 1182–1189.
62. Takasaki I, Takizawa T, Sugimoto K, Gotoh E, Shionoiri H, Ishii M. Effects of hypertension and aging on fibronectin expression in aorta of Dahl salt-sensitive rats. Am J Physiol. . 1994; 267: H1523–H1529.[Abstract/Free Full Text]
63. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Ishimura Y, Chatani F, Iwao H. Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-ß1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther. . 1995; 273: 509–515.
64. Himeno H, Crawford DC, Hosoi M, Chobanian AV, Brecher P. Angiotensin II alters aortic fibronectin independently of hypertension. Hypertension. . 1994; 23: 823–826.[Abstract/Free Full Text]
65. Ford CM, Li S, Pickering JG. Angiotensin II stimulates collagen synthesis in human vascular smooth muscle cells. Involvement of the AT₁ receptor, transforming growth factor-ß, and tyrosine phosphorylation. Arterioscler Thromb Vasc Biol. . 1999; 19: 1843–1851.[Abstract/Free Full Text]
66. Tharaux PL, Chatzaiantoniou C, Fakhouri F, Dussaule JC. Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. Hypertension. . 2000; 36: 330–336.[Abstract/Free Full Text]
67. Otsuka S, Sugano M, Makino N, Sawada S, Hata T, Niho Y. Interaction of mRNAs for angiotensin II type I and type 2 receptors to vascular remodeling in spontaneously hypertensive rats. Hypertension. . 1998; 32: 467–472.[Abstract/Free Full Text]
68. Levy BI, Benessiano J, Henrion D, Caputo L, Heymes C, Duriez M, Poitevin P, Samuel JL. Chronic blockade of AT₂-subtype receptors prevents the effects of angiotensin II on the rat vascular structure. J Clin Invest. . 1996; 98: 418–425.[Medline] [Order article via Infotrieve]
69. Mifune M, Sasamura H, Shimizu-Hirota R, Miyazaki H, Saruta T. Angiotensin II type 2 receptors stimulate collagen synthesis in cultured vascular smooth muscle cells. Hypertension. . 2000; 36: 845–850.[Abstract/Free Full Text]
70. Itoh H, Mukoyama M, Pratt RE, Gibbons GH, Dzau VJ. Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest. . 1993; 91: 2268–2274.
71. Li Q, Muragaki Y, Hatamura I, Ueno H, Ooshima A. Stretch-induced collagen synthesis in cultured smooth muscle cells from rabbit aortic media and a possible involvement of angiotensin II and transforming growth factor-ß. J Vasc Res. . 1998; 35: 93–103.[Medline] [Order article via Infotrieve]
72. Schlumberger W, Thie M, Rauterberg J, Robenek H. Collagen synthesis in cultured aortic smooth muscle cells. Modulation by collagen lattice culture, transforming growth factor-beta 1, and epidermal growth factor. Arterioscler Thromb. . 1991; 11: 1660–1666.[Abstract/Free Full Text]
73. O’Callaghan CJ, Williams B. Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells: role of TGF-ß1. Hypertension. . 2000; 36: 319–324.[Abstract/Free Full Text]
74. Bray P, Agrotis A, Bobik A. Transforming growth factor-beta and receptor tyrosine kinase-activating growth factors negatively regulate collagen genes in smooth muscle of hypertensive rats. Hypertension. . 1998; 31: 986–994.[Abstract/Free Full Text]
75. Benetos A, Lacolley P, Safar ME. Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. . 1997; 17: 1152–1156.[Abstract/Free Full Text]
76. Rizvi MA, Katwa L, Spadone DP, Myers PR. The effects of endothelin-1 on collagen type I and type III synthesis in cultured porcine coronary artery vascular smooth muscle cells. J Mol Cell Cardiol. . 1996; 28: 243–252.[Medline] [Order article via Infotrieve]
77. Tharaux PL, Chatziantoniou C, Casellas D, Fouassier L, Ardaillou R, Dussaule JC. Vascular endothelin-1 gene expression and synthesis and effect on renal type I collagen synthesis and nephroangiosclerosis during nitric oxide synthase inhibition in rats. Circulation. . 1999; 99: 2185–2191.[Abstract/Free Full Text]
78. Boffa JJ, Tharaux PL, Placier S, Ardaillou R, Dussaule JC, Chatziantoniou C. Angiotensin II activates collagen type I gene in the renal vasculature of transgenic mice during inhibition of nitric oxide synthesis: evidence for an endothelin-mediated mechanism. Circulation. . 1999; 100: 1901–1908.[Abstract/Free Full Text]
79. Ammarguellat F, Larouche I, Schiffrin EL. Myocardial fibrosis in DOCA-salt hypertensive rats: effect of endothelin ET_A receptor antagonism. Circulation. . 2001; 103: 319–324.[Abstract/Free Full Text]
80. Park JB, Schiffrin EL. ET_A receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats. Hypertension. . 2001; 37: 1444–1449.[Abstract/Free Full Text]
81. Park JB, Schiffrin EL. Effect of ET_A receptor antagonist on hypertrophy and collagen deposition in heart and aorta in response to chronic aldosterone infusion. Amer J Hypertens. . 2001; 14: 133A. Abstract.
82. Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Unemori EN, Lark MW, Amento E, Libby P. Cytokine-stimulated human smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res. . 1994; 75: 181–189.[Abstract/Free Full Text]
83. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. . 1994; 94: 2494–2503.
84. Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR. Matrix metalloproteinases and diseases of the CNS. Trends Neurosci. . 1998; 21: 75–80.[Medline] [Order article via Infotrieve]
85. Diez J, Panizo A, Gil MJ, Monreal I, Hernandez M, Pardo Mindan J. Serum markers of collagen type I metabolism in spontaneously hypertensive rats: relation to myocardial fibrosis. Circulation. . 1996; 93: 1026–1032.[Abstract/Free Full Text]
86. Diez J, Hernandez M. Is the extracellular degradation of collagen type I fibers depressed in spontaneously hypertensive rats with myocardial fibrosis? Circulation. . 1996; 94: 2998.
87. Diez J, Laviades C, Mayor G, Gil MJ, Monreal I. Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation. . 1995; 91: 1450–1456.[Abstract/Free Full Text]
88. Laviades C, Varo N, Fernandez J, Mayor G, Gil MJ, Monreal I, Diez J. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation. . 1998; 98: 535–540.[Abstract/Free Full Text]
89. Intengan HD, Schiffrin EL. Collagen degradation is diminished in mesenteric arteries of spontaneously hypertensive rats after hypertension is established. Hypertension. . 1999; 34: 329. Abstract.
90. Hein M, Fisher J, Kim DK, Hein L, Pratt RE. Vascular smooth muscle phenotype influences glycosaminoglycan composition and growth effects of extracellular matrix. J Vasc Res. . 1996; 33: 433–441.[Medline] [Order article via Infotrieve]
91. Castro CM, Cruzado MC, Miatello RM, Risler NM. Proteoglycan production by vascular smooth muscle cells from resistance arteries of hypertensive rats. Hypertension. . 1999; 34: 893–896.[Abstract/Free Full Text]
92. Hahn AW, Kern F, Jonas U, John M, Buhler FR, Resink TJ. Functional aspects of vascular tenascin-C expression. J Vasc Res. . 1995; 32: 162–174.[Medline] [Order article via Infotrieve]
93. Fogerty FJ, Akiyama SK, Yamada KM, Mosher DF. Inhibition of binding of fibronectin to matrix assembly sites by anti-integrin (_5ß1) antibodies. J Cell Biol. . 1990; 111: 699–708.[Abstract/Free Full Text]
94. Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM. Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Circ Res. . 1994; 74: 214–224.[Abstract/Free Full Text]
95. Gadeau AP, Campan M, Millet D, Candresse T, Desgranges C. Osteopontin overexpression is associated with arterial smooth muscle cell proliferation in vitro. Arterioscler Thromb. . 1993; 13: 120–125.[Abstract/Free Full Text]
96. Benetos A, Lacolley P, Safar ME. Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. . 1997; 17: 1152–1156.
97. Nishikawa K. Angiotensin AT₁ receptor antagonism and protection against cardiovascular end-organ damage. J Hum Hypertens. . 1998; 12: 301–309.[Medline] [Order article via Infotrieve]
98. Tsoporis J, Keeley FW, Lee RM, Leenen FH. Arterial vasodilation and vascular connective tissue changes in spontaneously hypertensive rats. J Cardiovasc Pharmacol. . 1998; 31: 960–962.[Medline] [Order article via Infotrieve]

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