Prevention of stenosis after vascular reconstruction: Pharmacologic control of intimal hyperplasia—A review
1991; Elsevier BV; Volume: 13; Issue: 6 Linguagem: Inglês
10.1016/0741-5214(91)90055-y
ISSN1097-6809
Autores Tópico(s)Lipoproteins and Cardiovascular Health
ResumoMost diseased blood vessels can be reconstructed as long as there is reasonable inflow and outflow distal to the stenotic or occluded segment. All forms of reconstruction, whether they directly attack the occluding lesion (endarterectomy, angioplasty), or bypass it (vein or prosthetic bypass), cause injury and a wound healing response.1Ip JH Fuster V Badimon L Badimon J Taubman MB Chesebro JH. Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation.J Am Coll Cardiol. 1990; 15: 1667-1687Abstract Full Text PDF PubMed Scopus (699) Google Scholar, 2Clowes AW. Pathologic intimal hyperplasia as a response to vascular injury and reconstruction.in: Vascular surgery. WB Saunders Company, Philadelphia1989: 266-275Google Scholar Although necessary for long-term function, this wound healing response can also be the cause of luminal narrowing and ultimate failure of the reconstruction. In this review we will define the scope of the problem and provide a brief description of the biology of the injury response as well as a survey of the current thinking regarding pharmacologic control of restenosis. Luminal narrowing as a result of excessive intimal hyperplasia is a particular problem after carotid endarterectomy,3Clagett GP. Morphogenesis and clinicopathologic characteristics of recurrent carotid disease.J Vasc Surg. 1986; 3: 10-23PubMed Scopus (111) Google Scholar, 4Healy DA Zierler RE Nicholls SC et al.Long-term follow-up and clinical outcome of carotid restenosis.J Vasc Surg. 1989; 10: 662-669PubMed Scopus (150) Google Scholar femoropopliteal vein bypass,5Whitremore AD Clowes AW Couch NP Mannick JA. Secondary femoropopliteal reconstruction.Ann Surg. 1981; 193: 35-42Crossref PubMed Scopus (346) Google Scholar superficial femoral angioplasty or atherectomy,6Johnston KW Rae M Hogg-Johnston SA et al.5-year results of a prospective study of percutaneous transluminal angioplasty.Ann Surg. 1987; 206: 403-413Crossref PubMed Scopus (433) Google Scholar and coronary angioplasty.7Liu MW Roubin GS King SB. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia.Circulation. 1989; 79: 1374-1387Crossref PubMed Google Scholar The stenosing intimal lesions tend to appear during the first 6 months after surgery. On gross examination they are white, firm, and fibrous and are not associated with thrombus; at late times (more than 2 years), they can accumulate thrombus and resemble the primary atherosclerotic plaque.3Clagett GP. Morphogenesis and clinicopathologic characteristics of recurrent carotid disease.J Vasc Surg. 1986; 3: 10-23PubMed Scopus (111) Google Scholar To the extent these lesions reduce blood flow and cause ischemia, they produce symptoms; hence, a recurrent stenosis in the coronary circulation will cause angina, whereas a recurrent stenosis in an operated carotid artery usually is asymptomatic. It is extremely difficult to obtain more than a sketchy outline of the arterial injury response in man since the operated vessels are rarely approached except when the new intimal lesions are large and flow-reducing. Thus much of what we know about injury is based on studies in animal models (Fig. 1). In the rat passage of a balloon embolectomy catheter along the common carotid artery strips away the endothelium and damages the media.8Clowes AW Reidy MA Clowes MM. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium.Lab Invest. 1983; 49: 327-333PubMed Google Scholar, 9Clowes AW Reidy MA Clowes MM. Mechanisms of stenosis after arterial injury.Lab Invest. 1983; 49: 208-215PubMed Google Scholar In our hands such damage destroys approximately 20% of the smooth muscle cells (SMCs). Platelets adhere to the wall as soon as blood flow is restored. In the rat the platelet layer is established within minutes of the time of injury. When examined by scanning electron microscopy the platelets appear to form a monolayer, and thrombi rarely develop in this model, although they are present in other rat models (nylon filament denudation). If the injured vessel has a prior history of disease (atherosclerosis, previous injury, and intimal thickening), the thrombotic response tends to be much more pronounced.10Groves HM Kinlough-Rathbone RL Richardson M Jorgensen L Moore S Mustard JF. Thrombin generation and fibrin formation following injury to rabbit neointima. Studies of vessel wall reactivity and platelet survival.Lab Invest. 1982; 46: 605-612PubMed Google Scholar Approximately 24 hours after carotid balloon injury, a fraction (approximately 20% to 30%) of the medial SMCs start synthesizing deoxyribonucleic acid (DNA) (as determined by incorporation of tritiated thymidine).11Clowes AW Schwartz SM. Significance of quiescent smooth muscle migration in the injured rat carotid artery.Circ Res. 1985; 56: 139-145Crossref PubMed Scopus (491) Google Scholar The stimulated cells appear to respond in synchrony since the maximum thymidine labeling index occurs at 33 hours and is approximately equal to the growth fraction during the first week.12Majesky MW Schwartz SM Clowes MM Clowes AW. Heparin regulates smooth muscle S phase entry in the injured rat carotid artery.Circ Res. 1987; 61: 296-300Crossref PubMed Scopus (152) Google Scholar Several days after injury SMCs start migrating from the media to the intima. Although many of these cells are proliferating, some are not. Nondividing, migrating SMCs can be identified in rat carotid arteries exposed to a continuous infusion of tritiated thymidine by the absence of nuclear labeling in autoradiographic preparations. Based on the measured growth fraction, the number of nondividing cells, and the total accumulation of SMCs over 2 weeks, we have concluded that the nondividing cells might account for 50% of the cells migrating across the intimal elastic lamina.11Clowes AW Schwartz SM. Significance of quiescent smooth muscle migration in the injured rat carotid artery.Circ Res. 1985; 56: 139-145Crossref PubMed Scopus (491) Google Scholar Why some migrating SMCs proliferate and others do not is not understood, although there is some indication that this difference might, in part, be controlled by endogenous factors (see herein).13Hansson GK Jonasson I Holm J Clowes MM Clowes AW. Gamma interferon regulates vascular smooth muscle proliferation and Ia espression in vitro and in vivo.Circ Res. 1988; 63: 712-719Crossref PubMed Scopus (221) Google Scholar Once in the intima, SMCs continue to proliferate to form a thick layer. In regions covered early by regenerating endothelium, the proliferation of intimal SMCs is brought to a halt sooner than in regions lacking an endothelium. Nevertheless, even in regions never covered by endothelium, SMC growth eventually stops (approximately 4 weeks) and does not cause occlusion of the vessel. The luminal surface is formed by modified SMCs, which possess some, but not all, of the properties of endothelium.14Clowes AW Clowes MM Reidy MA. Kinetics of cellular proliferation after arterial injury. III. Endothelial and smooth muscle growth in chronically denuded vessels.Lab Invest. 1986; 54: 295-303PubMed Google Scholar, 15Clowes AW Collazzo RE Karnovsky MJ. A morphologic and permeability study of luminal smooth muscle cells after arterial injury in the rat.Lab Invest. 1978; 39: 141-150PubMed Google Scholar In general the cells form a surface that is free of adherent platelets, but unlike endothelium the cellular junctions are quite permeable and do not exclude large molecules. The intima is further enlarged by the accumulation of extracellular matrix synthesized by the SMCs. A stable state is reached at approximately 3 months at which point the matrix accounts for 80% of the intimal volume.9Clowes AW Reidy MA Clowes MM. Mechanisms of stenosis after arterial injury.Lab Invest. 1983; 49: 208-215PubMed Google Scholar After 3 months, the structure of the intima does not appear to change. Like SMC proliferation, endothelial proliferation begins immediately after injury. The new endothelial monolayer is formed by ingrowth of cells from untraumatized artery proximal and distal to the zone of denudation. The cells at the growing edge divide, whereas those farther back resume the resting state. The growing edge advances initially at an approximate rate of 0.2 mm/day but stops spontaneously after 8 to 12 weeks at approximately 10 to 12 mm, even though the central portion of the rat carotid artery remains uncovered.16Reidy MA Clowes AW Schwartz SM. Endothelial regeneration. V. Inhibition of endothelial regrowth in arteries of rat and rabbit.Lab Invest. 1983; 49: 569-575PubMed Google Scholar Why rat endothelial cells stop growing is not known, but it appears to be a property common to endothelium from several different species including man.17Clowes AW Kirkman TR Clowes MM. Mechanisms of arterial graft failure. II. Choronic endothelial and smooth muscle cell proliferation in healing polytetrafluoroethylene prosetheses.J Vasc Surg. 1986; 3: 877-884PubMed Scopus (133) Google Scholar How cellular growth is regulated in injured arteries is not known, although the foregoing description provides several clues. For example, the original “reaction-to-injury hypothesis” is based on these observations: (1) platelet adherence and degranulation precede SMC proliferation; (2) intimal thickening in injured arteries of thrombocytopenic animals is reduced18Friedman RJ Stemerman MB Wenz B et al.The effect of thrombocytopenia on experimental atherosclerotic lesion formation in rabbits. Smooth muscle cell proliferation and re-endothelialization.J Clin Invest. 1977; 60: 1191-1201Crossref PubMed Scopus (202) Google Scholar; and (3) platelet granules contain potent mitogens for cultured SMCs.19Ross R Glomset J Kariya B Harker L. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro.Proc Natl Acad Sci USA. 1974; 71: 1207-1210Crossref PubMed Scopus (1295) Google Scholar, 20Ross R Glomset JA. The pathogenesis of atherosclerosis.N Engl J Med. 1976; 295: 369-377Crossref PubMed Scopus (1471) Google Scholar Based on these observations Ross and Glomset20Ross R Glomset JA. The pathogenesis of atherosclerosis.N Engl J Med. 1976; 295: 369-377Crossref PubMed Scopus (1471) Google Scholar, 21Ross R Glomset JA. The pathogenesis of atherosclerosis.N Engl J Med. 1976; 295: 420-425Crossref PubMed Scopus (928) Google Scholar suggested that a high local concentration of growth factors, particularly platelet-derived growth factor (PDGF), released from degranulating platelets could stimulate SMC proliferation. Their hypothesis emphasizes the relationship between thrombosis and subsequent cell growth and vessel repair. A number of clinical and animal studies have been designed to test this hypothesis by use of pharmacologic inhibitors of platelet aggregation to inhibit intimal hyperplasia.22Clowes AW. The role of aspirin in enhancing arterial graft patency.J Vasc Surg. 1986; 3: 381-385PubMed Scopus (31) Google Scholar, 23Clagett GP Genton E Salzman EW. Antithrombotic therapy in peripheral vascular disease.Chest. 1989; 95: 128S-139SPubMed Google Scholar In general these drugs (for example, aspirin) have little or no effect on platelet adherence. They also have very little impact on restenosis after injury. We have reexamined this hypothesis in ballooned carotid arteries of rats made transiently thrombocytopenic.24Fingerle J Johnson R Clowes AW Majesky MW Reidy MA. Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery.Proc Natl Acad Sci USA. 1989; 86: 8412-8416Crossref PubMed Scopus (347) Google Scholar In these experiments a single dose of antiplatelet antibody reduced the platelet count in the blood and the number of platelets adherent to denuded artery to 5% of control. Expression of ornithine decarboxylase messenger ribonucleic acid (mRNA) at 6 hours and thymidine labeling were the same in thrombocytopenic and control animals, yet surprisingly the thickening in the thrombocytopenic animals at 1 week was substantially reduced. We have concluded from these results that platelet factors do not play a substantial role in the initial wave of SMC proliferation after injury but do influence migration from the media to the intima. This conclusion is supported by our recent data demonstrating that intravenous infusion of PDGF BB, the predominant form of PDGF in rat platelets, is a very weak stimulant of SMC proliferation.25Jawien A Lindner V Bowen-Pope DF Schwartz SM Reidy MA Clowes AW. Clowes AW. Platelet-derived growth factor (PDGF) stimulates arterial smooth muscle cell proliferation in vivo.FASEB J. 1990; 4 ([Abstract]): 342Google Scholar If platelets do not cause the initial wave of SMC proliferation, what does? We gain some insight into a possible mechanism when we make a comparison of the response to different forms of carotid injury.26Clowes AW Clowes MM Fingerle J Reidy MA. Regulation of smooth muscle cell growth in injured artery.J Cardiovasc Pharmacol. 1989; 14: S12-S15PubMed Google Scholar Balloon catheterization of the artery produces a substantial SMC proliferative response at 48 hours (approximately 15% thymidine labeling index),8Clowes AW Reidy MA Clowes MM. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium.Lab Invest. 1983; 49: 327-333PubMed Google Scholar whereas nylon wire endothelial denudation increases it only to 2%.27Fingerle J Au YPT Clowes AW Reidy MA. Intimal lesion formation in rat carotid arteries after endothelial denudation in the absence of medial injury.Arteriosclerosis. 1990; 10: 1082-1087Crossref PubMed Google Scholar Balloon catheterization significantly damages the medial SMCs, whereas nylon wire denudation does not. Both techniques completely strip away the carotid endothelium. From these observations, Lindner and Reidy (Addendum) have concluded that damaged SMCs might be releasing some kind of intracellular factor that would then stimulate the remaining SMCs. A logical candidate is basic fibroblast growth factor (bFGF), since it can be released from disrupted cultured vascular cells and is a growth factor for SMCs in vitro. Evidence now exists that bFGF is an important regulator of SMC growth in vivo, since infusion of this mitogen into rats subjected to carotid injury produces a substantial increase in SMC proliferation, and treatment with an antibody to bFGF blocks SMC proliferation by approximately 80% (unpublished results). The mRNA for other known growth promoting factors such as PDGF (in this case, PDGF A),28Majesky M Reidy M Benditt EP Schwartz S. Expression of platelet-derived growth factor (PDGF) A- and B-chain gene in smooth muscle during repair of arterial injury.J Mol Cell Cardiol. 1987; 19: S3Abstract Full Text PDF PubMed Google Scholar, 29Majesky MW Daemen MJAP Schwartz SM. Alpha1-Adrenergic stimulation of platelet-derived growth factor A-chain gene expression in rat aorta.J Biol Chem. 1990; 265: 1082-1088Abstract Full Text PDF PubMed Google Scholar, 30Majesky MW Reidy MA Bowen-Pope DF Hart CE Wilcox JN Schwartz SM. PDGF ligand and receptor gene expression during repair of arterial injury.J Cell Biol. 1990; 111: 2149-2158Crossref PubMed Scopus (362) Google Scholar transforming growth factor beta (unpublished results), and insulin-like growth factor I (IGF I)31Cercek B Fishbein MC Forrester JS Helfant RH Fagin JA. Induction of insulin-like growth factor I messanger RNA in rat aorta after balloon denudation.Circ Res. 1990; 66: 1755-1760Crossref PubMed Scopus (170) Google Scholar are expressed by medial SMCs in ballooned rat artery. What role those factors play in the SMC response to injury is not known, although for cultured SMCs, they are important mitogens. Hemodynamic factors also influence SMC proliferation and intimal thickening. Decreased blood flow and increased blood pressure cause an increase in intimal thickening.32Clowes AW Clowes MM. Influence of chronic hypertension on injured and uninjured arteries in spontaneously hypertensive rats.Lab Invest. 1980; 6: 535-541Google Scholar, 33Kohler TR Jawien A Clowes AW. Effect of shear on intimal hyperplasia following arterial injury in rats.Circulation. 1990; 82 ([Abstract]): 400Google Scholar The mechanism by which mechanical forces on the wall are transduced into a biochemical and biologic response is not known. In part, at least the response might be mediated by a renin-angiotensin mechanism since angiotensin converting enzyme and angiotensin II receptor inhibitors reduce intimal hyperplasia in the rat carotid injury model,34Powell JS Clozel JP Muller RKM et al.Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury.Science. 1989; 245: 186-188Crossref PubMed Scopus (1034) Google Scholar and angiotensin II infusion stimulates SMC proliferation and reverses the effect of the converting enzyme inhibitor, cilazapril (J. S. Powell: personal communication). Smooth muscle cells in injured artery might stop growing simply because the supply of bFGF or other mitogens has been exhausted. On the other hand, certain molecules might also be responsible for actively inhibiting proliferation. The studies of Hansson et al.13Hansson GK Jonasson I Holm J Clowes MM Clowes AW. Gamma interferon regulates vascular smooth muscle proliferation and Ia espression in vitro and in vivo.Circ Res. 1988; 63: 712-719Crossref PubMed Scopus (221) Google Scholar provide strong evidence that gamma interferon synthesized by a small number of T lymphocytes in the injured artery causes neighboring SMCs to express class II major histocompatibility antigens (Ia) and inhibits SMC proliferation. Most of the Ia-positive SMCs in the intima are not labeled by tritiated thymidine and are the cells we referred to earlier as the migrating but nondividing medial SMCs. These observations raise the possibility that other kinds of lymphocyte-derived cytokines such as interleukin I might also be active in the wall. We noted earlier that SMCs stop proliferating as soon as the overlying endothelium is regenerated. This observation might be accounted for by the restoration of a permeability barrier and a lack of nutrients entering the wall. Alternatively, the regenerated endothelial cells might release an inhibitor of SMC growth. One such inhibitor is heparan sulfate. The related molecule, heparin, in pharmacologic amounts inhibits SMC growth and migration in vitro and in vivo.35Clowes AW Karnovsky MJ. Suppression by heparin of smooth muscle cell proliferation in injured arteries.Nature. 1977; 265: 625-626Crossref PubMed Scopus (623) Google Scholar, 36Clowes AW Clowes MM. Kinetics of cellular proliferation after arterial injury. IV. Heparin inhibits rat smooth muscle mitogenesis and migration.Circ Res. 1986; 58: 839-845Crossref PubMed Scopus (207) Google Scholar Cultured endothelial cells and SMCs synthesize and secrete a species of heparan sulfate, which when released from the native proteoglycan inhibits SMC growth.39Fritze LMS Reilly CF Rosenberg RD. An antiproliferative heparan sulfate species produced by postconfluent smooth muscle cells.J Cell Biol. 1985; 100: 1041-1049Crossref PubMed Scopus (219) Google Scholar, 40Castellot Jr, JJ Addonizio ML Rosenberg R Karnovsky MJ. Cultured endothelial cells produce a heparin-like inhibitor of smooth muscle cell growth.J Cell Biol. 1981; 90: 372-379Crossref PubMed Scopus (492) Google Scholar, 41Castellot Jr., JJ Favreau LV Karnovsky MJ Rosenberg RD. Inhibition of vascular smooth muscle cell growth by endothelial cell-derived heparin. Possible role of a platelet endoglycosidase.J Bio Chem. 1982; 257: 11256-11260PubMed Google Scholar Heparin also markedly alters the composition of the extracellular matrix by decreasing elastin and interstitial collagen and increasing proteoglycans.42Snow AD Bolender RP Wight TN Clowes AW. Heparin modulates the composition of the extracellular matrix domain surrounding arterial smooth muscle cells.Am J Pathol. 1990; 137: 313-330PubMed Google Scholar Whether locally-synthesized heparan sulfate in the injured artery influences SMC function is not known. In summary, the formation of an intimal thickening after vascular injury depends on SMC proliferation, migration, and matrix synthesis and is regulated by positive and negative factors from the blood, leukocytes, and the vascular wall cells themselves (Fig. 2). During the last 2 decades, we have recognized intimal hyperplasia to be a response common to all forms of vascular injury incurred during vascular reconstruction. In small vessels it is a major cause of restenosis and thrombosis. Our attempts to inhibit it by pharmacologic means have largely met with failure, and at present small vessel reconstructions can be salvaged only if rigorous surveillance is maintained in the postoperative period and the recurrent lesion corrected surgically or by angioplasty. The original reaction to injury hypothesis relating platelet-aggregation, release of platelet mitogens, and subsequent intimal hyperplasia has had a substantial influence on clinical strategies to control restenosis. The principal objective has been inhibition of platelet aggregation by use of drugs such as aspirin and dipyridamole.22Clowes AW. The role of aspirin in enhancing arterial graft patency.J Vasc Surg. 1986; 3: 381-385PubMed Scopus (31) Google Scholar Such an antithrombotic approach has improved patency in aortocoronary bypass grafts from approximately 80% to 90% at 1 year after operation, although several major trials have not shown benefit. It appears from a comparison of the various studies that the drugs must be started within the first 48 hours after operation; if started at some later time, then there is no benefit from drug therapy when patency is assessed 1 year after operation. These drugs have been of no benefit in patients undergoing coronary angioplasty.43Schwartz L Lesperance J Bourassa MG et al.The role of antiplatelet agents in modifying the extent of restenosis following percutaneous transluminal coronary angioplasty.Am Heart J. 1990; 119: 232-236Abstract Full Text PDF PubMed Scopus (38) Google Scholar, 44Fanelli C Aronoff R. Restenosis following coronary angioplasty.Am Heart J. 1990; 119: 357-368Abstract Full Text PDF PubMed Scopus (71) Google Scholar In the peripheral circulation, aspirin and dipyridamole are of limited benefit.23Clagett GP Genton E Salzman EW. Antithrombotic therapy in peripheral vascular disease.Chest. 1989; 95: 128S-139SPubMed Google Scholar A slight improvement occurs in patency of synthetic femoropopliteal grafts and vein femorotibial grafts, but the effect is not dramatic and not reproducible between trials. Whether these drugs are inhibiting intimal hyperplasia or are simply reducing the incidence of acute thrombosis is not clear. In animal models of arterial grafting or angioplasty, antithrombotic treatment has a variable effect on intimal hyperplasia. Aspirin and related drugs inhibit platelet aggregation and have little effect on platelet adherence. Since a drastic change in platelet numbers has only a modest effect on formation of the intimal lesion, it seems unlikely that potent inhibitors of platelet adherence will be an improvement over aspirin and might very well cause significant bleeding. Several alternative pharmacologic approaches to the problem of intimal hyperplasia are suggested by recent animal studies. Treatment with fish oil reduces platelet aggregation, cell synthesis of PDGF, and diminishes intimal thickening in animal models.44Fanelli C Aronoff R. Restenosis following coronary angioplasty.Am Heart J. 1990; 119: 357-368Abstract Full Text PDF PubMed Scopus (71) Google Scholar, 45Goodnight SH Fisher M Fitzgerald GA Levine PH. Assessment of the therapeutic use of dietary fish oil in atherosclerotic vascular disease and thrombosis.Chest. 1989; 95: 19S-25SPubMed Google Scholar Unfortunately, clinical studies of fish oil in patients undergoing coronary angioplasty report both positive and negative results, and no definitive conclusion can be drawn. Calcium channel blockers also inhibit intimal hyperplasia in experimental animal models but have little effect on restenosis after coronary angioplasty.46Schlant RC King III., SB Usefulness of calcium entry blockers during and after percutaneous transluminal coronary artery angioplasty.Circulation. 1989; 80: IV88-IV92PubMed Google Scholar, 48Jackson CL Bush RC Bowyer DE. Mechanism of antiatherogenic action of calcium antagonists.Atherosclerosis. 1989; 80: 17-26Abstract Full Text PDF PubMed Scopus (97) Google Scholar Other unrelated drugs such as prednisone and azathioprine appear to work in animal models but have not been tested in man. Our own experimental studies and those of several other laboratories provide strong support for the clinical investigation of two classes of pharmacologic agents, angiotensin-converting enzyme (ACE) inhibitors and heparin-like drugs.34Powell JS Clozel JP Muller RKM et al.Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury.Science. 1989; 245: 186-188Crossref PubMed Scopus (1034) Google Scholar, 49Powell JS Müller RKM Rouge M Kuhn H Hefti F Baumgartner HR The proliferative response to vascular injury is suppressed by angiotensin-converting enzyme inhibition.J Cardiovasc Pharmacol. 1990; 16: S42-S49Crossref PubMed Scopus (101) Google Scholar, 50Clowes AW Clowes MM. Regulation of smooth muscle proliferation by heparin in vitro and in vivo.Int Angiol. 1987; 6: 45-51PubMed Google Scholar We pointed out earlier that the administration of the ACE inhibitor, cilazapril, blocks intimal thickening in balloon-injured rat carotid arteries and that the specific angiotensin II receptor antagonist, Dup 753, has the same effect. The intravenous infusion of angiotensin II largely reverses the effect of orally administered cilazapril (J. S. Powell and H. R. Baumgartner: personal communication). Where angiotensin II is generated and how it acts to stimulate SMC proliferation is not known. Nevertheless, sufficient experience is available with ACE inhibitors as antihypertensive drugs to recommend their trial for this new purpose. Two large clinical trials are in progress to test whether cilazapril can inhibit restenosis after coronary angioplasty. If cilazapril proves to be effective, then there will be considerable interest in investigating the use of ACE inhibitors in other vascular beds. Since the SMC proliferative response to injury in man is likely to be short lived, we would anticipate that the pharmacologic inhibitors will be needed for no more than 2 to 3 months. Heparin blocks intimal hyperplasia by inhibiting SMC proliferation,12Majesky MW Schwartz SM Clowes MM Clowes AW. Heparin regulates smooth muscle S phase entry in the injured rat carotid artery.Circ Res. 1987; 61: 296-300Crossref PubMed Scopus (152) Google Scholar, 36Clowes AW Clowes MM. Kinetics of cellular proliferation after arterial injury. IV. Heparin inhibits rat smooth muscle mitogenesis and migration.Circ Res. 1986; 58: 839-845Crossref PubMed Scopus (207) Google Scholar, 38Hoover RL Rosenberg R Haering W Karnovsky MJ. Inhibition of rat arterial smooth muscle cell proliferation by heparin. II. in vitro studies.Circ Res. 1980; 47: 578-583Crossref PubMed Scopus (274) Google Scholar, 51Clowes AW Clowes MM. Kinetics of cellular proliferation after arterial injury II. Inhibition of smooth muscle growth by heparin.Lab Invest. 1985; 52: 611-616PubMed Google Scholar SMC migration,37Majack RA Clowes AW. Inhibition of vascular smooth muscle cell migration by heparin-like glycosaminoglycans.J Cell Physiol. 1984; 118: 253-256Crossref PubMed Scopus (164) Google Scholar as well as altering the composition of the pericellular matrix.42Snow AD Bolender RP Wight TN Clowes AW. Heparin modulates the composition of the extracellular matrix domain surrounding arterial smooth muscle cells.Am J Pathol. 1990; 137: 313-330PubMed Google Scholar The action of heparin does not depend on its anticoagulant activity since heparin fragments that do not bind to antithrombin III are as effective as mature, full length heparin.52Guyton JR Rosenberg RD Clowes AW Karnovsky MJ. Inhibition of rat arterial smooth cell proliferation by heparin. I. in vivo studies with anticoagulant and non-anticoagulant heparin.Circ Res. 1980; 46: 625-634Crossref PubMed Scopus (333) Google Scholar, 53Clowes AW Rosenberg RD Clowes MM. Regulation of arterial smooth cell proliferation by heparin in vivo.Surg Forum. 1983; 34: 357-360Google Scholar Heparin also stimulates endothelial regeneration. Although a number of structural elements including length and sulfation are important for optimal inhibitory activity,54Castellot Jr, JJ Choay J Lormeau JC Petitou M Sache E Karnovsky MJ. Structural determinants of the capacity of heparin to inhibit the proliferation of vascular smooth muscle cells. II. Evidence for a pentasaccharide sequence that contains a 3-O-sulfate group.J Cell Biol. 1986; 102: 1979-1984Crossref PubMed Scopus (134) Google Scholar, 55Castellot Jr, JJ Beeler DL Rosenberg RD Karnovsky MJ. Structural determinants of the capacity of heparin to inhibit the proliferation of vascular smooth muscle cells.J Cell Physiol. 1984; 120: 315-320Crossref PubMed Scopus (135) Google Scholar no clear mechanism of action has been worked out to account for the various heparin effects summarized above. One possibility is that heparin binds bFGF released from the injured SMCs and endothelial cells and prevents local accumulation in the matrix. An alternative possibility for which we have developed considerable evidence is that heparin interferes with the ability of the SMC to degrade its surrounding matrix, a necessary event for proliferation and migration to occur. Both in vitro and in vivo, heparin decreases the expression of tissue-type plasminogen activator and at least in vitro displaces urokinase from the cell layer into the medium.56Clowes AW Clowes MM Au YPT Kenagy R. Heparin inhibits tissue plasminogen activator expression in injured rat carotid artery.FASEB J. 1990; 4 ([Abstract]): 480Google Scholar, 57Au YPT Clowes AW. Effect of heparin on interstitial collagenasc and tissue plasminogen activator expression.J Cell Biol. 1990; 111 ([Abstract]): 234Google Scholar In addition, heparin inhibits the expression interstitial collagenase. The effect of heparin on collagenase and tissue-type plasminogen activator expression appears to be at the level of transcription. Although the mechanism of action of heparin is not established, nevertheless sufficient data exist to support the use of low anticoagulant or possibly nonanticoagulant heparin fractions as inhibitors of restenosis. Several lower molecular weight fractions that largely lack antithrombin but still possess anti-Xa activity are in clinical use for prophylaxis against deep venous thrombosis. In general these forms of heparin also have significant antiproliferative activity. Although they need to be given parenterally, our studies in the rat model indicate that a brief course of therapy is of long-term benefit.36Clowes AW Clowes MM. Kinetics of cellular proliferation after arterial injury. IV. Heparin inhibits rat smooth muscle mitogenesis and migration.Circ Res. 1986; 58: 839-845Crossref PubMed Scopus (207) Google Scholar A note of a caution is in order. Repeated injection of large doses of heparin fragments can produce transient anticoagulation. We have observed that if repeated cycles of anticoagulation and coagulation are allowed to occur because of infrequent heparin injections, the injured carotid segments can develop thrombosis. Hence, any clinical strategy needs to produce a reasonable steady state low level of anticoagulation. Alternatively, we should wait until nonanticoagulant heparin becomes available. From the experimental data we have concluded the heparin treatment would need to be started within the first 24 hours after surgery and continued for the period of maximal proliferation.12Majesky MW Schwartz SM Clowes MM Clowes AW. Heparin regulates smooth muscle S phase entry in the injured rat carotid artery.Circ Res. 1987; 61: 296-300Crossref PubMed Scopus (152) Google Scholar In rats, 7 days of heparin is as effective as 28 days of treatment.36Clowes AW Clowes MM. Kinetics of cellular proliferation after arterial injury. IV. Heparin inhibits rat smooth muscle mitogenesis and migration.Circ Res. 1986; 58: 839-845Crossref PubMed Scopus (207) Google Scholar Finally, we have recently found that heparin in combination with orally administered cilazapril produces a greater inhibition of intimal hyperplasia than heparin alone (unpublished results). Intimal hyperplasia is part of the reparative process that takes place in arteries after all forms of reconstruction. In some instances it is excessive and causes luminal narrowing, reduction in blood flow, and thrombosis. A critical feature of the intimal lesion is the accumulation of SMCs. The migration and proliferation of these cells during intimal thickening appears to be regulated by factors from the blood (particularly platelets and leukocytes) and the vascular wall cells themselves. In experimental animal models, pharmacologic inhibition of smooth muscle growth leads to a reduction in intimal thickening, and we are hopeful that a pharmacologic approach based on these results will prove effective in preventing restenosis in man.
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