Professional Documents
Culture Documents
Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis
Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis
Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis
AbstractRemodeling 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.
Downloaded from http://hyper.ahajournals.org/ by guest on October 11, 2017
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. (Hypertension. 2001;38[part 2]:581-587.)
Key Words: arteries apoptosis inflammation fibrosis collagen muscle, smooth
Received March 27, 2001; first decision June 5, 2001; revision accepted July 18, 2001.
Metabolic Research Unit/Diabetes Center, University of California at San Francisco (H.D.I.); and Clinical Research Institute of Montreal (E.L.S.),
Montreal, Qubec, 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@itsa.ucsf.edu
2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
581
582 Hypertension September 2001 Part II
mentia and has been reported to different degrees in athero- artery SMCs.36 During early treatment, ACE inhibition, AT1
sclerosis, restenosis, myocardial infarction, and heart failure. receptor antagonism, and Ca2 channel blockade stimulated
Apoptosis is increased in hypertensive rat heart,1316 brain,13 medial SMC apoptosis in thoracic aortae of SHR, although
kidney,13,17 and arteries, where smooth muscle cell (SMC) mere blood pressure lowering by hydralazine had no effect.37
death modulates remodeling.18,19 Aortae of DOCA-salt rats,20 Some studies suggested that apoptosis occurs in waves for
SHR,21 and angiotensin-infused rats22 exhibit apoptosis de- limited periods.19,34,37 In other studies, increased apoptotic
tectable by DNA laddering, augmented in situ end-labeling of rate persisted through 12 weeks of treatment with enalapril
fragmented DNA, and/or Bax/Bcl-2 ratio. Vascular SMC and amlodopine21 and through 16 weeks with quinapril.38
cells in hypertensive rats are more prone to apoptosis, as Increased apoptosis also occurs in aortae of DOCA-salt rats,
shown by serum deprivation of aortic SMC from stroke-prone and treatment with ETA-selective endothelin receptor antag-
SHR (SHR-sp).23 In SHR, by 8 and 12 weeks but not 4 weeks onists enhances apoptosis in this model.19 Antihypertensive
of age, blood pressure, small artery media/lumen ratio, and therapy may therefore contribute to regression of vascular
apoptosis were increased.24 Enhanced apoptosis in resistance wall growth via activation of pro-apoptotic mechanisms.
arteries may be bed specific. In SHR small intramyocardial
arteries, the Bax/Bcl-2 ratio was reduced, suggesting de- Inflammation
creased apoptosis,25 whereas arterioles and capillaries were The actions of Ang II are mediated in large measure by
more prone to apoptosis, suggesting that in these beds, stimulation of production of superoxide anion and activation
apoptosis influences vascular resistance via rarefaction, as in of redox-sensitive genes.39 Some of these include genes
Downloaded from http://hyper.ahajournals.org/ by guest on October 11, 2017
V are in endothelial and SMC basement membranes.58 There collagen synthesis. Collagen synthesis was inhibited by
are early reports47,48 of increased collagen synthesis in the TGF- neutralizing antibody or truncated TGF- type II
arterial wall in hypertension that occurred globally in SHR receptor, suggesting a linear pathway where Ang stimulates
and DOCA-salt rat aortae, mesenteric arteries, cerebral mi- TGF- secretion, which in turn triggers collagen synthesis.
crovessels, pial arteries, and basilar arteries. Collagen accu- Indeed, exogenous TGF- in aortic SMC results in collagen
mulation may not follow synthesis and may be bed specific, synthesis,72 and in human cells, a role of TGF- in stretch-
as it occurs in coronary arteries49 but less consistently in induced collagen synthesis was also detected.73 However, in
aortae of SHR50 or DOCA-salt rats,51 although recent studies SHR SMC these effects of TGF- were blunted versus
report increases in collagen III but not collagen I in Japanese WKY.74
and Lyon SHR strains.52 In SHR-sp aortae, total collagen is Other modulators of collagen synthesis include aldosterone
not augmented.53 Nonetheless, upregulated gene expression and endothelin. Aortic collagen accumulation was attenuated
of types I, III, and IV was detected in aortae and mesenteric by inhibiting ACE21 or by antagonizing aldosterone.75 Colla-
arteries.54 Collagen was reported increased in mesenteric gen I synthesis is stimulated by endothelin-1 (ET-1) in
small arteries of SHR55,56 or subcutaneous resistance arteries coronary artery SMC.76 Indeed, in the N-nitro-L-arginine
from essential hypertensive humans.57 Collagen is the extra- methyl ester (L-NAME) model of hypertension, ET-1 syn-
cellular fibrillar component that may alter the passive pres- thesis is increased in renal microvessels and activates local
sure/diameter relation of arteries at higher pressures and collagen formation.77 Losartan blocked L-NAMEinduced
induce a progressive stiffening of the vascular wall. However, fibrosis, and stimulatory effects of angiotensin on collagen
Downloaded from http://hyper.ahajournals.org/ by guest on October 11, 2017
we showed in small arteries from these relatively young I-2 chain promoter activity were attenuated by endothelin
humans with mild to moderate hypertension that increased receptor antagonism.78 In DOCA-salt hypertensive rats,
collagen deposition may be associated with reduced stiff- which have very significant cardiac fibrosis, administration of
ness.57 This indicates that it is not the amount of collagen in an ETA receptor antagonist ameliorated interstitial and
the wall but rather the recruitment of collagen fibers at higher perivascular fibrosis.79 In aldosterone-infused rats, vascular
pressures that results in increased stiffness of the vessel wall. changes were prevented by endothelin antagonism,80 and
Early in hypertension, both in experimental animals and in collagen deposition in heart and arteries was also demon-
humans, the vessel wall components may be less stiff in spite strated to be endothelin dependent.81 Cardiovascular fibrosis
of increased collagen deposition, but as hypertension is, in large part, a humoral-determined event, with central
progresses, other changes, particularly in extracellular ma- roles of Ang II, ET-1, and mineralocorticoids.
trixSMC anchoring, may result in normalization of wall Matrix metalloproteinase (MMP) activity may modulate
stiffness.58 Later, the increased stiffness that occurs in ad- hypertension-related accumulation of extracellular matrix pro-
vanced hypertension may develop.59 Fibronectin also accu- teins in resistance arteries. MMPs are Zn2- and Ca2-dependent
mulated in DOCA-salt,60 SHR,61 Dahl salt-sensitive,62 SHR- proteolytic enzymes that degrade extracellular matrix pro-
sp,63 and Ang IIinfused rat aortae,64 probably independently teins.82,83 Several different MMPs are present in the vasculature.
of blood pressure. In many of these models, stimulation of These include collagenases (eg, interstitial collagenase MMP-1
AT1 receptors is the likely mechanism. However, the extent to and MMP-13) that digest structural or fibrillar collagens (types
which fibronectin accumulates in resistance arteries in hyper- I to III). Gelatinases A (MMP-2) and B (MMP-9), which digest
tension is presently unclear, although we have preliminary denatured collagen (gelatin) and collagen types IV and V, are
evidence (Q. Pu and E.L. Schiffrin, unpublished, 2001) using found in the subendothelial basement membrane. Stromelysins
confocal microscopy that demonstrated increased fibronectin (eg, MMP-3) are also found. They digest adhesive molecules
in the media of resistance arteries of SHR-sp. such as laminin, fibronectin, nonfibrillar collagens, and proteo-
Ang II stimulates human vascular SMC production of glycans. Finally, there are the membrane-type MMPs (MT1-
collagen I,65 activating the procollagen type I gene via the MMP or MMP-14). MT1-MMP activates other MMPs.84 MT1-
mitogen-activated protein kinase/ERK pathway.66 These ef- MMP and MMP-2 act as an integral part of multiprotein
fects are mediated, at least in part, by AT1 receptors.62,64,65 enzymatic complex. MT1-MMP may activate latent MMP-13,
AT2 receptors may also play a role67,68 via GI proteins.69 which in turn activates MMP-9. MT1-MMP may form a ternary
Involvement of angiotensin evokes the possible involvement complex with tissue inhibitors of metalloproteinase (TIMP)-2
of multiple autocrine growth factors that modulate the re- and pro-MMP-2 that depends on the tethering of pro-MMP-2 by
sponses to angiotensin, such as transforming growth factor v3-integrin. Indeed, a number of integrins, including 51, may
(TGF-) and platelet-derived growth factor,70 as well as other be involved in activation of MMPs. MMP-mediated modulation
growth factors, including insulin-like growth factor and basic of extracellular matrix could result via integrin-mediated signal-
fibroblast growth factor. Ang II increased TGF- in a ing in cytoskeletal reorganization. This could contribute to both
losartan-sensitive manner, and in human arterial SMC, differential restructuring of extracellular matrix proteins and
angiotensin-stimulated collagen synthesis was inhibited by reorganization of SMCs in the vascular wall in hypertension. In
blocking TGF-.71 A relationship between Ang II and TGF- serum from SHR with extensive myocardial fibrosis85,86 and in
was suggested previously, in which stretch was the experi- humans with essential hypertension,87 markers of enhanced
mental stimulus of collagen synthesis in rabbit aortic SMC.72 synthesis of type I collagen are not balanced by markers of
Stretch concomitantly increased immunoreactive Ang II and increased type I collagen degradation. In hypertensive patients in
TGF- in the culture medium, and elicited collagen synthesis. whom type I collagen precursors were augmented, serum con-
Angiotensin antagonism attenuated TGF- secretion and centrations of MMP-1 were in fact reduced.88 MMP-1 activity
584 Hypertension September 2001 Part II
was decreased in the mesenteric arterial bed of young SHR from apoptosis. Fibronectin matrix assembly may likewise
before hypertension was established.89 MMP-3 activity was also facilitate vascular SMC growth. As mentioned previously,
decreased, which may promote accumulation of fibronectin and total fibronectin50 and 51-integrins50,55 are increased in
proteoglycans in SHR.90,91 Pro-MMP2 and activated MMP-2 arteries of SHR. This suggests that fibronectin matrix assem-
activities were diminished in mesenteric arteries from adult bly, which requires the interaction between the arginine-
SHR,89 which could facilitate accumulation of types IV and V glycine-aspartate site of fibronectin and 51-integrins,93 is
collagen and fibronectin.54 Changes in MMP activity may thus also elevated in SHR vessels. Another arginine-glycine-
contribute to resistance artery remodeling in hypertension by aspartate containing protein that may be associated with
modulating extracellular matrix profile and interacting with proliferation is osteopontin, a secreted glycoprotein adhesive
adhesion receptors. Significant decreases in MMP activity in for vascular SMCs via v3-integrins.94 In vitro studies have
young SHR-sp vessels could result in decreased collagen turn- demonstrated that osteopontin overexpression is associated
over and increased collagen accumulation, whereas in the older with arterial SMC proliferation.95
hypertensive rats, vascular increased MMP activity suggests
countervailing activation of MMPs or inhibition of activity of Fibrosis, Vascular Remodeling, and Therapy
TIMPs to reduce collagen accumulation in the vascular wall. Arterial wall thickening may increase peripheral resistance
We have proposed that remodeling of the small arteries and blood pressure, in part by physically encroaching on the
occurring in both humans and experimental models of hyper- lumen and, where collagen is invoked, by increasing wall
tension implies a remodeling of the extracellular matrix and stiffness to reduce lumen diameter at a given pressure.27 In
Downloaded from http://hyper.ahajournals.org/ by guest on October 11, 2017
of extracellularvascular SMC attachment sites and a restruc- SHR resistance arteries, collagen density or relative content
turing of vascular SMCs that may in part be triggered by the was normalized by ACE inhibition,55,56 AT1 receptor block-
adhesion molecules that mediate anchoring to ECM compo- ade,55 and the dihydropyridine Ca2-channel blocker amlo-
nents. These adhesion molecules (integrins) transduce signals dipine.56 Aldosterone antagonism also reduced collagen in
from the extracellular to the cytoskeletal fibrillar compo- SHR aortae.96 Likewise, in vessels from SHR-sp and DOCA-
nents.27 Because of changes in extracellular matrix compo- salt rats, AT1 receptor antagonism reduced collagen types I,
nents and corresponding adhesion receptors, interactions III, and IV mRNA.63,97 At least in SHR, amelioration of
between SMCs and matrix proteins shift, quantitatively collagen accumulation is not due to blood pressure lowering
and/or topographically, resulting in a rearrangement of SMCs per se, as minoxidil had no effect on collagen content in
and a restructured vascular wall. We hypothesized that aortae or in renal and superior mesenteric arteries.98 Thus,
vascular remodeling may involve changes in these attachment regression of vascular fibrosis may occur independently of
sites. We have shown that expression of integrins is abnormal blood pressure lowering.
in SHR blood vessels and is modulated by age.55 Mesenteric
arteries from SHR exhibited an increase in expression of Conclusion
v3- and 51-integrins from 6 to 20 weeks. In arteries from In hypertension, vascular remodeling contributes to increased
adult SHR, the volume density of collagen was significantly peripheral resistance, impacting both development and com-
increased.55 Bzie et al50 have also reported increases in plications of hypertension. Although growth is the mecha-
5-integrins and fibronectin, their main ligand, in aorta from nism that is more classically associated with vascular remod-
SHR. Such changes may represent an increase in cell eling, it has increasingly been appreciated that apoptosis,
extracellular matrix attachment sites and perhaps also their low-grade inflammation, and vascular fibrosis are dynamic
topographical localization that may modulate arterial struc- processes that also may influence the degree of remodeling
ture. One may envision that in the hypertensive state, pro- that occurs (summarized in the Figure). Inward growth may
gressive deposition of extracellular matrix fibrillar compo- be associated with peripheral apoptosis, contributing to eu-
nents anchored to SMCs of the chronically constricted vessel trophic remodeling. Low-grade inflammation, perhaps angio-
may result in an artery with a persistently smaller lumen, as tensin- or endothelin-dependent and triggered in part by
found in the inward eutrophic remodeling characteristic of increased oxidative stress in the vascular wall stimulated by
small arteries of SHR and in essential hypertension. In these peptides or other agents, may elicit growth factor
addition, changes in the attachment of the fibrillar elements of mediated extracellular matrix remodeling. Changes in the
the matrix may occur that contribute to arterial inward anchoring of cells to extracellular fibrillar components may
remodeling by altering the anchoring of SMC to fibrillar alter cell attachment, changing the architecture of the vessel
components of the extracellular matrix. This would also alter wall, and may promote abnormal intracellular transduction of
signal transduction by integrins from outside the cell to the extracellular input to the cytoskeleton of SMC, contributing
SMC cytoskeleton, promoting restructuring of the SMC in the to SMC cell restructuring. Chronic vasoconstriction may
vessel wall. result in an inwardly remodeled blood vessel as the con-
Growth of the smooth muscle in the media of blood vessels tracted vessel structure becomes embedded in a remodeled
may be facilitated by several extracellular matrix proteins. extracellular matrix, further promoting re-arrangement of
Tenascin-C, an extracellular matrix glycoprotein and ligand SMCs around a smaller lumen. Growth, apoptosis, inflamma-
for v3, is one such extracellular component that may be tion, and fibrosis of blood vessels may thus all contribute to
important in vascular remodeling in hypertension. It co- vascular remodeling. The resulting arterial remodeling may
localizes with proliferating SMCs in SHR92 and may be a initially be adaptive but eventually becomes maladaptive and
survival factor that promotes proliferation and protects SMCs compromises organ function, contributing to cardiovascular
Intengan and Schiffrin Vascular Remodeling in Hypertension 585
crine, paracrine, or autocrine) drive. Either directly or indirectly 10. Rizzoni D, Porteri E, Castellano M, Bettoni G, Muiesan ML, Muissan P,
via the action of vasoactive peptides such as Ang II and ET-1, Gaulini SM, Agabiti-Rosei E. Vascular hypertrophy and remodeling in
mediated in part by increased oxidative stress, vasoconstriction secondary hypertension. Hypertension. 1996;28:785790.
is induced and SMC growth and apoptosis, low-grade inflam- 11. Lee RMKW, Owens GK, Scott-Burden T, Head RJ, Mulvany MJ,
mation, and vascular fibrosis occur, leading to vascular remod- Schiffrin EL. Pathophysiology of smooth muscle in hypertension. Can
eling. Vascular remodeling may feed back by amplifying BP ele- J Physiol Pharmacol. 1995;73:574 584.
vation. SMC growth and apoptosis, low-grade inflammation, and 12. Thompson CB. Apoptosis in the pathogenesis and treatment of disease.
vascular fibrosis are dynamic processes that influence vessel Science. 1995;267:1456 1462.
remodeling. Inward growth associated with peripheral apoptosis 13. Hamet P, Richard L, Dam TV, Teiger E, Orlov SN, Gaboury L, Gossard
may lead to eutrophic remodeling. Low-grade inflammation, per- F, Tremblay J. Apoptosis in target organs of hypertension. Hypertension.
haps triggered by Ang II or ET-1 stimulation of oxidative stress 1995;26:642 648.
in the vascular wall, may promote growth factormediated 14. Diez J, Panizo A, Hernandez M, Vega F, Sola I, Fortuno MA, Pardo
extracellular matrix remodeling. Changes in the anchoring of J. Cardiomyocyte apoptosis and cardiac angiotensin-converting enzyme
cells to extracellular fibrillar components may alter extracellular- in spontaneously hypertensive rats. Hypertension. 1997;30:1029 1034.
SMC attachments (integrins), changing the architecture of the 15. Fortuno MA, Ravassa S, Etayo JC, Diez J. Overexpression of Bax protein
vessel wall, and the intracellular transduction of extracellular sig- and enhanced apoptosis in the left ventricle of spontaneously hyper-
nals to the SMC cytoskeleton, favoring restructuring of SMC tensive rats: effects of AT1 blockade with losartan. Hypertension. 1998;
cells. Changes in MMP/TIMPs may contribute to alteration in 32:280 286.
collagen turnover and promote extracellular matrix remodeling. 16. Liu JJ, Peng L, Bradley CJ, Zulli A, Shen J, Buxton BF. Increased
Chronic vasoconstriction may lead to embedding of the con- apoptosis in the heart of genetic hypertension, associated with increased
tracted vessel structure in a remodeled extracellular matrix, con- fibroblasts. Cardiovasc Res. 2000;45:729 735.
tributing to the inward remodeling of the blood vessel as SMCs 17. Rodriguez-Lopez AM, Flores O, Arevalo MA, Lopez-Novoa JM. Glo-
become rearranged around a smaller lumen. Growth, apoptosis,
merular cell proliferation and apoptosis in uninephrectomized sponta-
inflammation, and fibrosis in the blood vessel wall may thus all
neously hypertensive rats. Kidney Int Suppl. 1998;68:S36 S40.
contribute to vascular remodeling. Although not developed in
18. Cho A, Cantman DW, Langille BL. Apoptosis (programmed cell death)
the text, endothelial dysfunction, in part induced by BP eleva-
in arteries of the neonatal lamb. Circ Res. 1995;76:168 175.
tion and mediated by reduced NO bioavailability as NO is scav-
19. Hamet P, deBlois D, Dam TV, Richard L, Teiger E, Tea BS, Orlov SN,
enged by oxygen free radicals, also promotes remodeling. NO
Tremblay J. Apoptosis and vascular wall remodeling in hypertension.
would under normal conditions inhibit vasoconstriction, growth,
Can J Physiol Pharmacol. 1996;74:850 861.
and collagen deposition and promote apoptosis. Remodeling
20. Sharifi AM, Schiffrin EL. Apoptosis in aorta of deoxycorticosterone
may initially be adaptive but eventually becomes maladaptive
acetatesalt hypertensive rats: effect of endothelin receptor antagonism.
and compromises organ function, contributing to cardiovascular
J Hypertens. 1997;15:14411448.
complications of hypertension.
21. Sharifi AM, Schiffrin EL. Apoptosis in vasculature of spontaneously
hypertensive rats: effect of an angiotensin-converting enzyme inhibitor
complications of hypertension. Accordingly, growth, apopto- and a calcium channel antagonist. Am J Hypertens. 1998;11:1108 1116.
sis, inflammation, and fibrosis all are important end points 22. Diep QN, Li JS, Schiffrin EL. In vivo study of AT1 and AT2 angiotensin
and attractive therapeutic objectives in hypertensive vascular receptors in apoptosis of rat blood vessels. Hypertension. 1999;34:
disease. 617 624.
23. Devlin AM, Clark JS, Reid JL, Dominiczak AF. DNA synthesis and
apoptosis in smooth muscle cells from a model of genetic hypertension.
Acknowledgments Hypertension. 2000;36:110 115.
The authors work was supported by grants 13570 and 37917 and a 24. Rizzoni D, Rodella L, Porteri E, Rezzani R, Guelfi D, Piccoli A, Castellano
group grant to the Multidisciplinary Research Group on Hyperten- M, Muiesan ML, Bianchi R, Rosei EA. Time course of apoptosis in small
sion to E.L.S., all from the Canadian Institutes of Health Research resistance arteries of spontaneously hypertensive rats. J Hypertens. 2000;18:
(CIHR, previously Medical Research Council of Canada). H.D.I. 885891.
was supported by a Centennial Fellowship (now entitled Senior 25. Vega F, Panizo A, Pardo-Mindan J, Diez J. Susceptibility to apoptosis
Research Fellowship) from CIHR. measured by MYC, BCL-2, and BAX expression in arterioles and cap-
illaries of adult spontaneously hypertensive rats. Am J Hypertens. 1999;
References 12:815 820.
1. Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, 26. Gobe G, Browning J, Howard T, Hogg N, Winterford C, Cross R.
Schiffrin EL, Heistad DD. Vascular remodeling. Hypertension. 1996;28: Apoptosis occurs in endothelial cells during hypertension-induced micro-
505506. vascular rarefaction. J Struct Biol. 1997;118:6372.
586 Hypertension September 2001 Part II
27. Intengan HD, Schiffrin EL. Structure and mechanical properties of 50. Bzie Y, Lamaziere JM, Laurent S, Challande P, Cunha RS, Bonnet J,
resistance arteries in hypertension: role of adhesion molecules and extra- Lacolley P. Fibronectin expression and aortic wall elastic modulus in
cellular matrix determinants. Hypertension. 2000;36:312318. spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. 1998;
28. Dickhout JG, Lee RMKW. Apoptosis in the muscular arteries from young 18:10271034.
spontaneously hypertensive rats. J Hypertens. 1999;17:14131419. 51. Karam H, Heudes D, Gonzales MF, Loffler BM, Clozel M, Clozel JP.
29. Irani K. Oxidant signaling in vascular cell growth, death, and survival: a Respective role of humoral factors and blood pressure in aortic
review of the roles of reactive oxygen species in smooth muscle and remodeling of DOCA hypertensive rats. Am J Hypertens. 1996;9:
endothelial cell mitogenic and apoptotic signaling. Circ Res. 2000;87: 991998.
179 183. 52. Chamiot Clerc P, Renaud JF, Blacher J, Legrand M, Samuel JL, Levy BI,
30. Pollman MJ, Yamada T, Horiuchi M, Gibbons GH. Vasoactive sub- Sassard J, Safar ME. Collagen I and III and mechanical properties of
stances regulate vascular smooth muscle cell apoptosis: countervailing conduit arteries in rats with genetic hypertension. J Vasc Res. 1999;36:
influences of nitric oxide and angiotensin II. Circ Res. 1996;79:748 756. 139 146.
31. Yamada T, Horiuchi M, Dzau VJ. Angiotensin II type 2 receptor mediates 53. Mizutani K, Ikeda K, Kawai Y, Yamori Y. Biomechanical properties and
programmed cell death. Proc Natl Acad Sci U S A. 1996;93:156 160. chemical composition of the aorta in genetic hypertensive rats.
32. Cattaruzza M, Dimigen C, Ehrenreich H, Hecker M. Stretch-induced J Hypertens. 1999;17:481 487.
endothelin B receptormediated apoptosis in vascular smooth muscle 54. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y,
cells. FASEB J. 2000;14:991998. Ishimura Y, Chatani F, Iwao H. Angiotensin II type I receptor antagonist
33. Li PF, Maasch C, Haller H, Dietz R, von Harsdorf R. Requirement for inhibits the gene expression of transforming growth factor-1 and extra-
protein kinase C in reactive oxygen speciesinduced apoptosis of vascular cellular matrix in cardiac and vascular tissues of hypertensive rats.
smooth muscle cells. Circulation. 1999;100:967973. J Pharmacol Exp Ther. 1995;273:509 515.
34. Tea BS, Der Sarkissian S, Touyz RM, Hamet P, deBlois D. Proapoptotic 55. Intengan HD, Thibault G, Li JS, Schiffrin EL. Resistance artery
and growth-inhibitory role of angiotensin II type 2 receptor in vascular mechanics, structure, and extracellular components in spontaneously
smooth muscle cells of spontaneously hypertensive rats in vivo. Hyper- hypertensive rats: effects of angiotensin receptor antagonism and con-
Downloaded from http://hyper.ahajournals.org/ by guest on October 11, 2017
71. Li Q, Muragaki Y, Hatamura I, Ueno H, Ooshima A. Stretch-induced regions of human atherosclerotic plaques. J Clin Invest. 1994;94:
collagen synthesis in cultured smooth muscle cells from rabbit aortic 2494 2503.
media and a possible involvement of angiotensin II and transforming 84. Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR. Matrix
growth factor-. J Vasc Res. 1998;35:93103. metalloproteinases and diseases of the CNS. Trends Neurosci. 1998;21:
72. Schlumberger W, Thie M, Rauterberg J, Robenek H. Collagen synthesis 75 80.
in cultured aortic smooth muscle cells. Modulation by collagen lattice 85. Diez J, Panizo A, Gil MJ, Monreal I, Hernandez M, Pardo Mindan J.
culture, transforming growth factor-beta 1, and epidermal growth factor. Serum markers of collagen type I metabolism in spontaneously hyper-
Arterioscler Thromb. 1991;11:1660 1666. tensive rats: relation to myocardial fibrosis. Circulation. 1996;93:
73. OCallaghan CJ, Williams B. Mechanical strain-induced extracellular 1026 1032.
matrix production by human vascular smooth muscle cells: role of 86. Diez J, Hernandez M. Is the extracellular degradation of collagen type I
fibers depressed in spontaneously hypertensive rats with myocardial
TGF-1. Hypertension. 2000;36:319 324.
fibrosis? Circulation. 1996;94:2998.
74. Bray P, Agrotis A, Bobik A. Transforming growth factor-beta and
87. Diez J, Laviades C, Mayor G, Gil MJ, Monreal I. Increased serum
receptor tyrosine kinase-activating growth factors negatively regulate
concentrations of procollagen peptides in essential hypertension. Relation
collagen genes in smooth muscle of hypertensive rats. Hypertension. to cardiac alterations. Circulation. 1995;91:1450 1456.
1998;31:986 994. 88. Laviades C, Varo N, Fernandez J, Mayor G, Gil MJ, Monreal I, Diez J.
75. Benetos A, Lacolley P, Safar ME. Prevention of aortic fibrosis by spi- Abnormalities of the extracellular degradation of collagen type I in
ronolactone in spontaneously hypertensive rats. Arterioscler Thromb essential hypertension. Circulation. 1998;98:535540.
Vasc Biol. 1997;17:11521156. 89. Intengan HD, Schiffrin EL. Collagen degradation is diminished in mes-
76. Rizvi MA, Katwa L, Spadone DP, Myers PR. The effects of endothelin-1 enteric arteries of spontaneously hypertensive rats after hypertension is
on collagen type I and type III synthesis in cultured porcine coronary established. Hypertension. 1999;34:329. Abstract.
artery vascular smooth muscle cells. J Mol Cell Cardiol. 1996;28: 90. Hein M, Fisher J, Kim DK, Hein L, Pratt RE. Vascular smooth muscle
243252. phenotype influences glycosaminoglycan composition and growth effects
77. Tharaux PL, Chatziantoniou C, Casellas D, Fouassier L, Ardaillou R, of extracellular matrix. J Vasc Res. 1996;33:433 441.
Downloaded from http://hyper.ahajournals.org/ by guest on October 11, 2017
Dussaule JC. Vascular endothelin-1 gene expression and synthesis and 91. Castro CM, Cruzado MC, Miatello RM, Risler NM. Proteoglycan pro-
effect on renal type I collagen synthesis and nephroangiosclerosis during duction by vascular smooth muscle cells from resistance arteries of
nitric oxide synthase inhibition in rats. Circulation. 1999;99:21852191. hypertensive rats. Hypertension. 1999;34:893 896.
78. Boffa JJ, Tharaux PL, Placier S, Ardaillou R, Dussaule JC, Chatziantoniou C. 92. Hahn AW, Kern F, Jonas U, John M, Buhler FR, Resink TJ. Functional
Angiotensin II activates collagen type I gene in the renal vasculature of aspects of vascular tenascin-C expression. J Vasc Res. 1995;32:162174.
transgenic mice during inhibition of nitric oxide synthesis: evidence for an 93. Fogerty FJ, Akiyama SK, Yamada KM, Mosher DF. Inhibition of binding
endothelin-mediated mechanism. Circulation. 1999;100:19011908. of fibronectin to matrix assembly sites by anti-integrin (51) antibodies.
79. Ammarguellat F, Larouche I, Schiffrin EL. Myocardial fibrosis in J Cell Biol. 1990;111:699 708.
DOCA-salt hypertensive rats: effect of endothelin ET A receptor 94. Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM. Osteopontin
promotes vascular cell adhesion and spreading and is chemotactic for
antagonism. Circulation. 2001;103:319 324.
smooth muscle cells in vitro. Circ Res. 1994;74:214 224.
80. Park JB, Schiffrin EL. ETA receptor antagonist prevents blood pressure
95. Gadeau AP, Campan M, Millet D, Candresse T, Desgranges C.
elevation and vascular remodeling in aldosterone-infused rats. Hyper-
Osteopontin overexpression is associated with arterial smooth muscle cell
tension. 2001;37:1444 1449. proliferation in vitro. Arterioscler Thromb. 1993;13:120 125.
81. Park JB, Schiffrin EL. Effect of ETA receptor antagonist on hypertrophy 96. Benetos A, Lacolley P, Safar ME. Prevention of aortic fibrosis by spi-
and collagen deposition in heart and aorta in response to chronic aldo- ronolactone in spontaneously hypertensive rats. Arterioscler Thromb
sterone infusion. Amer J Hypertens. 2001;14:133A. Abstract. Vasc Biol. 1997;17:11521156.
82. Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Unemori EN, 97. Nishikawa K. Angiotensin AT1 receptor antagonism and protection
Lark MW, Amento E, Libby P. Cytokine-stimulated human smooth against cardiovascular end-organ damage. J Hum Hypertens. 1998;12:
muscle cells synthesize a complement of enzymes required for extra- 301309.
cellular matrix digestion. Circ Res. 1994;75:181189. 98. Tsoporis J, Keeley FW, Lee RM, Leenen FH. Arterial vasodilation and
83. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of vascular connective tissue changes in spontaneously hypertensive rats.
matrix metalloproteinases and matrix degrading activity in vulnerable J Cardiovasc Pharmacol. 1998;31:960 962.
Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis
Hope D. Intengan and Ernesto L. Schiffrin
Hypertension. 2001;38:581-587
doi: 10.1161/hy09t1.096249
Downloaded from http://hyper.ahajournals.org/ by guest on October 11, 2017
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/38/3/581
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.