Blood flow-induced remodeling of arteries in health and disease

Cardiovasc Pathol Vol. 1. No. 4 October-December 1992245-251

245

Blood Flow-Induced Remodeling of Arteries in Health and Disease B. Lowell

Langille,

PhD

From the Banting and Best Diabetes Centre and The Centre for Cardiovascular Research, Max Bell Research Centre, The Toronto Hospital and Department of Pathology, University of Toronto.

Vascular structures readily remodel in response to hemodynamic cues associated with changes in blood flows. These remodeling processes are invoked by a wealth of developmental, physiological, and pathological phenomena. Current work is providing novel clues concerning flow sensing by endothelial cells, the signal transduction pathways that translate flow detection into endothelial responses, and some of the signals that are transmitted to the effector cells, the vascular smooth muscle cells in the media. However, most of these mechanisms relate to acute responses to altered flow, and how important they are in eliciting tissue remodeling is unknown. Also, there is very little information on the processes that accomplish “remodeling,” beyond evidence that modulation of new tissue synthesis occurs. There is a potential for experiments in the near future to provide fundamental information on the genesis of the vascular structure-function relations, which now clearly spans much of the pre- and postnatal life.

to remodel whenever structures begin changes in time-averaged blood flows persist for more than a few days. These remodeling processes are critical to the regulation of arterial growth during development. Indeed a significant component of arterial growth regulation derives from vascular tissue sensitivity to local blood flow conditions. Furthermore many physiological adaptations, including those associated with chronic exercise programs, menstrual cycles, pregnancy and disuse atrophy, are associated with chronic changes in arterial blood flow rates and a coincident remodeling of the circulation (l-3). Finally, many vascular pathologies exhibit clinical manifestations because they chronically alter local blood flow rates, and the vascular remodeling that results can have a major impact on the progression of the disease state (4). In recent years, a substantial amount of information has been accumulated concerning the nature of flowinduced vascular remodeling; however, the processes by which vascular cells achieve appropriate structural Vascular

Manuscript received May 28, 1992, accepted May 28,19!32. Address for reprints: B Lowell Laqille, PhD, Max Bell Research Centre, The Toronto Hospital, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. 01992

by Elsevier Science Publishing

Co., Inc.

remodeling and the mechanisms that control them are poorly understood.

Remodeling

of Mature Arteries in Response to Altered Blood Flow

Adult vessels are capable of undergoing major remodeling, which can produce very substantial changes in vessel size when flow is chronically altered (Fig. 1). These diameter adjustments involve an acute vasomotor response (5-7), which is followed by medial restructuring when these flow changes persist. Acute phase. The acute vasodilation that occurs when flow increases appears to be mediated by endothelium through the release of endothelium-derived relaxing factor (EDRF, probably nitric oxide) (8,9). Constriction with decreased flow may be attributable in part to reductions in tonic release of EDRF, however, regrowth of denuded endothelium over arteries carrying subnormal flows causes the vessel to narrow in the re-endothelialized region, a response inconsistent with a net vasodilator effect of these cells (10). Therefore it appears that a constrictor may be released under low flow conditions in vivo. Also, constrictor re-

246

CardiovascPath01Vol. 1, No. 4 October-December1992:245-25 1

LANGILLE HEMODYNAMICS AND ARTERIAL REMODELING

sponses to decreased flow, at least in sheep carotids, take place over the first 24 hours after flow reduction (11) a time course that is much slower than that normally associated with EDRF-mediated responses (6). However, no in vivo data implicate a specific constrictor agonist in response to decreased flow. Available evidence argues against a role for prostanoids or a local renin-angiotensin response (12). Recent in vitro studies implicate enhanced endothelin release under low flow conditions (13). This very persistent vasoconstrictor is an attractive candidate for the early phases of remodeling responses, but in vivo support for its role is lacking at present. Chronic phase. Chronic adaptations to decreased flow entrench diameter decreases over a period of days to weeks; however, evidence for “remodeling” of wall tissues is largely functional rather than structural. Thus the arteries exhibit a smaller maximally dilated diameter and a smaller maximally constricted diameter than

do control vessels (14). Despite these functional changes, the arteries that exhibit this adaptation retain a contracted appearance when examined at the lightmicroscopic level. Arteries that carry decreased blood flow remodel without net changes in total collagen or elastin, the two major extracellular constituents in the arterial wall. Furthermore, total DNA contents are unaltered, a finding that suggests that no major changes in the population of the medial smooth muscle cells has occurred (14). The absence of net changes in cell number may simply reflect the very low turnover of mature vascular tissues, considering that about 0.1% to 0.01% of vascular cells replicate daily. Furthermore, the half-lives for elastin and collagen in arteries are also very long. The half-life for collagen in rat vessels is 60 to 90 days and elastin turns over extremely slowly, exhibiting a half-life that is generally comparable to the life span of the organism (15). By contrast with smooth muscle, a significant decrease in number of endothelial cells was detected 1 month after flow reduction in rabbit carotids (14). More recent data indicate that loss of endothelial cells occurs early and is readily apparent at 5 days (Walpola, A. I. Gotlieb, and B. L. Langille, unpublished data). This loss of endothelial cells prevents an increase in cell density on the luminal surface as the vessel narrows and surface area decreases. Physiologically, adaptations that maintain endothelial cell density as diameter decreases may characterize many adaptations that inFigure 1. A.

Vascular cast, prepared at physiological distending pressures, of the right renal artery-aortic junction of a normal rabbit. B. A similar cast from a rabbit prepared 6 months after right nephrectomy. Flow in the renal artery has been reduced from kidney plus adrenal flows to adrenal flows alone. C. Distal segment of renal artery shown in (Bb The cast includes the ligated stump of the renal artery and the proximal portion of the adrenal artery. Note that the diameter of the renal artery has decreased sufficiently to almost match that of the adrenal artery. From reference 40, by permission.

Cardiovasc Pathol Vol. 1, No. 4 October-December 1992:245-25 I

volve chronic alterations in blood flow. For example, Azmi and O’Shea (2) described deletion of endothelial cells during atrophy of the vascular supply to the corpus luteum during luteal regression. Endothelial deletion involved apoptosis of these cells, and those investigators suggested that it may result from the reduction in blood flow demands of luteal tissues at this time. At present, though, experimental evidence testing the role of flow in luteal vascular regression is lacking; it is also unknown whether apoptosis is the mechanism of endothelial cell deletion when blood flow is decreased experimentally. Proliferation of endothelium follows increases in flow. Interestingly, Masuda et al. (16) found that proliferation preceded the increases in vessel diameter that they observed following arteriovenous anastomosis; therefore it appeared to be a direct response to elevated flow (shear), rather than a secondary adaptation to these increases in size. The model used in the study caused very high flows, which probably induced turbulence, so more work is needed on flow changes within a physiological range. In general, wall remodeling with increased blood flow does not follow a pattern that is simply the reverse of that seen when flow decreases. First, diameter adjustments to reduce flow go to completion within a few days to 2 weeks. However, remodeling in response to increased flow is not initiated, apart from a modest vasodilator component (57), during the first month of increased flow (16). This may be because large arteries exhibit little resting vasomotor tone, so expansion through vasomotion is limited; by contrast, even relatively large arteries can reduce their diameters substantially by constricting (14). As a consequence, large arteries must rely largely on restructuring of wall constituents to increase vessel diameter. Experimental evidence suggests that responses to increased flow require net changes in medial tissue mass (17) unlike responses to decreased flow, although the specific wall constituents that are affected by increased flow have not been defined. There is no direct evidence concerning how early vasomotor responses to altered blood flow are entrenched by structural remodeling. As stated earlier our studies indicate that this is achieved without significant net changes in vessel wall elastin, collagen, or DNA contents (14). Furthermore, studies with 3H-thymidine indicate that smooth muscle turnover is not involved. We found that fewer than 0.03% of these cells were replicating per day, subsequent to flow reduction (unpublished data). It would appear inevitable, however, that remodeling involves some turnover of attachment sites between medial smooth muscle cells and surrounding matrix constituents as the vessel establishes a new resting diameter. Recent studies impli-

HEMODYNAMICS

AND ARTERIAL

LANGILLE REMODELING

247

cate urokinase and tissue plasminogen activator (uPA and tPA) in the reorganization of vascular cells’ interactions with matrix. Clowes and coworkers showed that both tPA and uPA are expressed as smooth muscle cells divide and then migrate to the intima following intimal-medial injury with a balloon catheter (18). The same enzymes may be involved in the structural remodeling that follows flow alterations. An additional possibility is that intracellular mechanisms in medial smooth muscle-perhaps turnover of contractile proteins-ultimately produces a contractile unit with a resting length shorter than that encountered in control vessels. Our observations favor this hypothesis (14). Histological examinations of arteries after adaptation to reduced flow suggested that reduced arterial diameters became entrenched without restoration of initial muscle cell length. Nevertheless, the vessel maximally contracted in diameter to 35% to 40% smaller than did control arteries in response to agonists. Thus it appears that the smooth muscle cells in these vessels could contract to much shorter cell lengths than those in control arteries. These vessels also exhibited smaller diameters (shorter cell lengths) when maximally dilated. These findings are consistent with a contractile apparatus that is at rest at shorter than normal cell lengths. Indeed, it is difficult to account for them without hypothesizing such remodelling of the contractile apparatus.

Blood Flow-Induced Remodeling Arterial Disease

and

Many vascular diseases produce clinical manifestations because blood flow is compromised; therefore flow-induced remodeling of arteries may result. In this case, the stimulus for remodeling is abnormal by definition, and the remodeling process may or may not be advantageous (19). In arterial occlusive disease, for example, the disease process can be affected at several levels. Initially, the lesion narrows the vessel lumen, and the resulting acceleration of blood flow through the lesion site elevates shear stress. Glagov et al. (20) showed that the medium ultimately expands during early lesion formation to maintain a normal lumen diameter. Thus it is probable that flow-induced adaptations limit encroachment on the vessel lumen early in lesion development. Ultimately, growth of the lesion compromises blood flow, and adjacent, healthy segments of the vessel wall experience reduced shear and may adapt by narrowing, a response that can increase resistance and exacerbate hypoperfusion. Finally, obstructive lesions partially depressurize the downstream vasculature and will therefore initiate flow through any collaterals arising from adjacent, pressurized vessels. If

Cdiovasc Path01Vol. 1, No. 4 October-December1!392%5-251

LANGILLE HEMODYNAMICS AND ARTERIAL REMODELING

248

I Cl

AORTIC CIRCUMFERENCE (mm)

10

0

THORACIC

131DAYS GESTATION 2-3 WEEKS POST PARTUM

L

ABDOMINAL

Figure 2. Internal circumferences of thoracic and abdominal aortas at 131 days of gestation (solid bars) and 2-3 weeks postpartum (open bars). Data were derived from morphometry of histological cross-sections prepared from vessels that were fixed at physiological pressures. *Indicates statistically significantly different from fetal circumferences. From reference 26, with permission.

vessels behave like other arteries that have been studied to date, they will expand in response to this flow stimulus. Consequently, collateral growth can be directly enhanced by the hemodynamic consequences of vessel occlusion. Because pathological changes in blood flow induce vascular remodeling that may affect progression of the disease state, it is important to assess the reversibility of this remodeling if flow is restored to normal. My colleague and I developed experimental models to chronically reduce blood flow in rabbit carotid arteries and then to restore these. flows to normal (21). Normal structure returned within 1 week of restoration of normal flows even after 2 months of flow reduction. Thus it appears that successful therapeutic interventions in the clinical setting may reverse adverse adaptations of adjacent vasculature.

collateral

Blood flow and vascular development Remodeling of the embryonic circulation. The hypothesis that developmental changes in blood flow are important in embryonic vascular development dates back over a century. Thoma (22) observed that the channels within the developing area vasculature that carried the greatest flows enlarged to become conduit vessels, whereas those that carry modest flows frequently regress, and he inferred that flow stimulated growth of embryonic vessels. Subsequent observations (23-25) supported this hypothesis, which has become entrenched in the embryonic literature. It is clear, however, that growth versus regression of embryonic vessels cannot be attributed solely to sensitivity to local hemodynamic conditions. For example, the orderly development of the embryonic aortic arches could not proceed solely on the basis of hemodynamic cues, because large, low-resistance shunts between the ventral

and dorsal aorta (e.g. the first aortic arch) regress whereas small, high-resistance shunts (e.g. the third arch) enlarge. The perinatal period. The weeks surrounding birth represent a particularly interesting period because very large and abrupt developmental changes in blood flow occur at parturition. At the same time, the many metabolic and hormonal changes that occur may elicit a unique growth modulation that overrides hemodynamic effects. In studies using perinatal sheep preparations, we found that the largest change in blood flow seen in a major vessel at parturition is a 95% decrease in the subrenal abdominal aorta, which supplies very high flows to the placenta in utero. The dramatic decrease in blood flow is accompanied by a marked reduction in diameter of the vessel (Fig. 2) and a near arrest of wall tissue accumulation that lasts for at least 3 weeks (26). This response is vessel-specific, considering that the thoracic aorta shows substantial growth over the same period. The thoracic aorta is also deprived of placental blood flow at birth, but this change is rapidly offset by much increased perfusion of visceral tissues via the celiac, superior mesenteric, and renal arteries, which arise upstream of the subrenal aorta. Subsequently we showed that arterial growth, and specifically elastin accumulation, in the weeks following birth correlates with blood flow changes (M. P. Bendeck and B. L. Langille, unpublished, data). However, an intriguing, flow-independent modulation of arterial growth occurs in the week surrounding birth (27). At that time, there is a very rapid aortic elastin and collagen accumulation (27) that is unrelated to blood flow changes (Fig. 3). The stimulus that drives this rapid connective tissue synthesis is unknown, but it may serve to preadapt arteries to the large increases in pressure that follow parturition. In sheep, arterial pressure rises from about 45 mmHg in near-term fetuses to about 65 mmHg at 3 weeks of age (27). If rapid perinatal connective tissue accumulation is an adaptation related to this pressure elevation, then there may be important implications for the preterm fetus that undergoes elective delivery. Do bleeding disorders in these neonates occur, in part, because elective delivery precludes rapid perinatal elastin and collagen accumulation in blood vessels? Postnatal arterial growth. Arterial growth remains sensitive to blood how throughout postnatal development. This sensitivity of arterial structure to blood flow is unlike flow-induced remodeling of adult arteries because both increases and decreases in blood flow influence wall tissue contents. When flows are manipulated in the subnormal range, accumulation of both smooth muscle cells and elastin are affected (14). When reductions in common carotid blood flows were induced in the weanling rabbit by ligating the external carotid,

CardiovascPathol Vol. 1, No. 4 October-December 1992:245-25 1

249

LANGILLE HEMODYNAMICS AND ARTERIAL REMODELING

Elaslin

A

mglcm Figure 3. Graphs showing elastin (A and C) and collagen (B and D) contents per cm of vessel length of abdominal (A and B) and thoracic (C and D) aorta of fetal and neonatal sheep at 120 and 140 days of gestation and at 3 and 21 days postpartum. Term is approximately 145 days. *Compared with values at 140 days gestation, p < 0.05. From reference 27, with permission.

‘i/

;i;

*bdo~;al

B

‘;I

:‘;

’

120

140

3

21

v’

li0

Age (days)

DNA and elastin contents were substantially lower than those of control vessels 1 month later. However, when flows are experimentally manipulated at levels above the normal range, smooth muscle growth is relatively unaffected but elastin accumulation continues to be modulated (di Stefano and B. L. Langille, unpublished data).

Shear Stress and Vascular Remodeling Substantial progress has been made at understanding the flow-sensing mechanism(s) of endothelium, with evidence pointing toward shear stress-sensitive potassium channels (28) and shear strain-related modulation of delivery of ATP-derived purines to the endothelial surface (29,30). The latter mechanism appears possible because of the presence of ectonucleotidases on the endothelial cell surface that degrade the active forms of vasoactive purines. Thus a shear ratedependent balance between delivery and degradation can be modulated by local flow conditions. The significance of these mechanisms remains unclear. Shear rate-dependent phenomena, which affect transport of materials to the wall, are fundamentally different from those driven by shear stress, which affect forces exerted on the luminal surface of the vessel. At a basic level, the two mechanisms have different implications. Shear stress-dependent effects imply that increases in viscosity of the flow medium will elicit effects that resemble the consequences of increased flow rates, because both changes increase shear stress. By contrast, shear rate-dependent effects are in theory diminished if viscosity increases, given that diffusion coefficients decrease in more viscous media. Unfortunately, applying these concepts to flow transduction in vivo is difficult because of both pulsatile flow and the cellular nature of blood. Changes in plasma viscosity

140

j

Age (day.9

probably have the previously described effects, but changes in blood viscosity attributable to altered hematocrit are more complex, given that the effects of red cells on transport of materials like ATP near the vessel wall are poorly understood. Safe inferences probably cannot be drawn at present; consequently, evidence that increases in blood viscosity result in vessel enlargement (31,32) do not allow conclusions concerning flow-sensing mechanisms.

Processes Involved in Vessel Wall Remodeling Little is known concerning how arterial growth and remodeling are controlled subsequent to signal transduction. It is not even clear, for example, whether a persistent change in vasomotor tone is an adequate stimulus to induce structural remodeling. Furthermore, the role of endothelium-derived growth modulators is also unclear. Shear stress influences production of platelet-derived growth factor (PDGF), at least in vitro (33) possibly through mechanisms that involve a “shear stress response element” in the promoter region of the PDGF (34). However, it is difficult to reconcile the vasodilator responses to increased shear with the putative vasoconstrictor actions of PDGF (35). Indeed, the bulk of available evidence concerning many agonists links vasoconstriction with growth stimulation and vasodilation with growth inhibition (35-38). Recent data suggest that fibroblast growth factor (FGF), a potent mitogen for both endothelium and vascular smooth muscle, is a vasodilator (39) but nothing is known about the shear sensitivity of FGF expression. Although some of the changes in the major wall constituents that occur during flow-induced remodeling have been defined, the processes involved in reorgan-

250

CardiovascPath01Vol. 1, No. 4 October-December1992~245-25 1

LANGILLE HEMODYNAMICS AND ARTERIAL REMODELING

izing these tissues remain unclear. How, for example, are newly synthesized tissues incorporated into the artery wall to increase vessel circumference in preference to increasing wall thickness, and what mechanisms differentiate this flow-induced remodeling from the wall thickening that occurs in hypertension? What is the role of matrix degradation in restructuring of the media? Furthermore, what is the role, if any, of apoptosis of vascular smooth muscle in these processes? This mode of cell death is important in the remodeling of many tissues, including vascular endothelium (2) but little evidence pertains to apoptosis of smooth muscle. Recently my colleague and I provided evidence that smooth muscle cell replication much exceeds that needed to account for DNA accumulation in the aortic smooth muscle postpartum (27) a finding that implicates substantial cell turnover during postnatal development. The fate of cells that are deleted from the vessel wall and their role in remodeling is unknown. The author is a career investigator of the Heart and Stroke Foundation of Ontario. Research reported in this paper was supported by the Heart and Stroke Foundation of Ontario and the Medical Research Council of Canada.

References 1. Chew HB, Segal SS. Hindlimb unloading alters conduit artery morphology. FASEB J 1990;4:A722. 2. Azmi TI, O’Shea JD. Mechanism of deletion of endothelial cells during regression of the corpus luteum. Lab Invest 1984;51:206217. 3. Hart MV, Morton MJ, Hosenpud JD, Metcalfe J. Aortic function during normal human pregnancy. Am J Obstet Gynecol 1986; 154887-891. 4. Langille BL, Gotlieb AI, Kim DW. Vascular tissue response to experimentally altered local blood flow conditions. In: Westerhof N, Gross DR, eds. Vascular Dynamics. New York: Plenum Press, 1989;229-235. 5. Schretzenmayr A. Uber Kreislaufregulatorische Vorgange an den grossen Arterien bei der Muskelarbeit. Pfhtgers Archiv Gesamte Physiol 1933;232:743-748. 6. Hintze TH, Vatner SF. Reactive dilation of large coronary arteries in conscious dogs. Circ Res 1984;54:5&57. 7. Lie M, Sejersted OM, Kiil F. Local regulation of vascular cross section during changes in femoral arterial blood flow in dogs. Circ Res 1970;27:727-737. 8. Kaiser L, Hull SS Jr., Sparks HV Jr. Methylene blue and ETYA block flow-dependent dilation in canine femoral artery. Am J Physiol 1986;250:H974-H981. 9. Diamond SL, Sharefkin JB, Dieffenbach C, Frasier-Scott K, McIntire LV, Eskin SG. Tissue plasminogen activator messenger RNA levels increase in cultured human endothelial cells exposed to laminar shear stress. J Cell Physiol 1990;143:36&371. 10. Jamal A, Bendeck M, Langille BL. Structural changes and recovery of function after arterial injury. Arteriosclerosis and Thrombosis 1992;12:307-317.

11

Langille BL. Remodeling of developing and mature arteries: endothelium, smooth muscle and matrix. J Cardiovasc Pharmacol (in press).

12 Langille BL. Bendeck MP. Arterial responses to compromised blood flow. Toxic01 Path01 (in press) 13 Sharefkin JB, Diamond SL, Eskin SG, McIntire LV, Dieffenbach CW. Fluid flow decreases preproendothelin mRNA levels and suppresses endothelin-1 peptide release in cultured human endothelial cells. J Vast Surg 1991;14:1-9. 14 Langille BL, Bendeck, MP Keeley FW. Adaptations of carotid arteries of young and mature rabbits to reduced carotid blood flow. Am J Physiol 1989;256:H931-H939. 15. LeFevre M, Rucker RB. Aortic elastin turnover in normal and hypercholesterolemic Japanese quail. Biochim Biophys Acta 1980;630:519-529. 16. Masuda H, Kawamura K, Tohda K, Shozawa T, Sageshima M, Kamiya A. Increase in endothelial cell density before artery enlargement in flow-loaded canine carotid artery. Arteriosclerosis 1989;9:812-823. 17. Zarins CK, Zatina MA, Giddens DP, Ku DN, Glagov S. Shear stress regulation of artery lumen diameter in experimental atherogenesis. J Vast Surg 1987;5:413420. 18. Clowes AW, Clowes MM, Au YPT, Reidy MA, Belin D. Smooth muscle cells express urokinase during mitogenesis and tissue-type plasminogen activator during migration in injured rat carotid artery. Circ Res 1990,67:61-67. 19. Langille BL. Hemodynamic factors and vascular disease. In: Silver MD., ed. Cardiovascular Pathology. New York: Churchill Livingstone, 1991;131-154. 20. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316:1371-1375. 21. Langille BL, Brownlee RD. Arterial adaptations to altered blood flow. Can J Physiol Pharmacol (in press). 22. Thoma R. Untersuchagen uberdie Histogenese und Histomechanik des Gefassystems, Stuttgart Enke, 1893. 23. Rychter Z. Experimental morphology of the aortic arches and heart loop in chick embryos. Adv Morphog 1962;2:333. 24. Stephan, F. Les suppleances obtenues experimentalement dam le systeme des arcs aortiques de l’embryon d’oiseau. Comptes Rendu 1949;36:647-651. 25. Clark ER. Studies on the growth of blood-vessels in the tail of the frog larva--by observation and experiment on the living animal. Am J Anat 1918;23:37-88. 26. Langille BL, Brownlee RD, Adamson SL. Perinatal aortic growth in lambs: relation to blood flow changes at birth. Am J Physiol 1990,259:H1247-H1253. 27. Bendeck MP, Langille BL. Rapid accumulation of elastin and collagen in the aortas of sheep in the immediate perinatal period. Circ Res 1991;69:1165-1169. 28. Olesen S-P, Clapham DE, Davies PF. Haemodynamic shear stress activates a K++ current in vascular endothelial cells. Nature 1988;221:168-170. 29. Dull RO, Davies PF. Flow modulation of agonist (ATP)response (CaZ+) coupling in vascular endothelial cells. Am J Physiol 1991;261:H149-H154. 30. MO M, Eskin SG, Schilling WP. Flow-induced changes in Ca2+ signaling of vascular endothelial cells: effect of shear stress and ATP. Am J Physiol 1991;260:H1698-H1707. 31. Levenson J. Flaud P, Del Pino M, Simon A. Blood viscosity as a chronic contributing factor of vasodilatation in humans. J Hypertens 1990;8:1049-1055. 32. Melkumyants AM, Balashov SA, Khayutin VM. Control of arterial hydraulic resistance by shear stress on endothelium. In: First World Congress of Biomechanics. City: Publisher, 1990, II: 27 (abstract)

Cardiovasc Path01 Vol. 1, NO. 4 October-December 1992245-251

LANGILLE HEMODYNAMICS AND ARTJZRJAL REMODELING

251

33. Hsieh H-J, Li N-Q, Frangos JA. Shear stress increases endotheIial platelet-derived growth factor mRNA levels. Am J Physiol 1991;26o:H642-H646.

37. Geisterfer, AAT, Owens, GK. Arginine vasopression-induced hypcrtrophy of cultured rat aortic smooth muscle cells. Hypertension 198!&14:413-420.

34. Resnick N, Dewey CF, Atkinson W, Cohins T, Gimbrone MA Jr. Shear stress regulates endothelial PDGF-B chain expression via induction of novel transcription factors. FASEB J 1992$ A1592.

38. Geisterfer AAT, Peach MJ, Owens, GK. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cehs. Circ Res 1988,62:74%756.

35. Berk BB, Alexander RW, Brock TA, Gimbrone MA Jr, Webb RC. Vasoconstriction: a new activity for platelet-derived growth factor. Science 1986,232:87-90. 36. Berk BC, Brock TA, Webb RC, et al. Epidermal growth factor, a vascular smooth muscle mitogen, induces rat aortic contraction. J Clin Invest 1985:75:1083-1086.

39. Cnevas P, CarceIIer F, Ortega S, Zazo M, Nieto I, GimenezGalIego G. Hypotensive activity of fibroblast growth factor. Science 1991;2541208-1210. 40. DuIing BR, Hogan RD, LangiIle BL, et al. Vasomotion control: functional hyperemia and beyond. Fed Proc 1987,46:251-263.