Sage Journals: Discover world-class research

Abstract

The authors have previously shown that cell-matrix interactions mediated via the matrix protein ligand vitronectin derived from serum and its cell surface αVβ₃ integrin receptor regulate migration of human aortic smooth muscle cells (SMC) in vitro. Arginine-glycine- aspartic acid (RGD) sequence of vitronectin (residues 45 to 47) is the critical domain for interactions. In this study the authors sought to determine whether interference with vitronectin-receptor interaction in the arterial wall would alter development of neoin timal hyperplasia in a rabbit model.

After balloon-induced injury of the carotid artery (2 fr Fogarty, three times) vitronectin was observed in the intima and upper third of the media (immunostaining, n= 3). In 6 rabbits the vitronectin receptor antagonist cyclic RGD peptide (1 mM) was locally applied to the injured artery by use of ethylene vinyl acetate copolymers (25%). RAD peptide (1 mM, n=6) and ethylene vinyl acetate copolymer without peptide (n=6) served as an inactive control. At twenty-eight days rabbits were killed, carotid arteries were fixed, and mean intima and media area was determined by computer-assisted planimetry. (continued on next page) (Abstract continued) The mean intima/media ratio in control balloon-injured arteries without peptide was 0.43 ±0.08 (SD). In injured RAD peptide-treated arteries the ratio was 0.39 ±0.09 (P= NS). In injured, cyclic RGD peptide-treated arteries the intima/media ration was 0.14 ±0.02 (P < 0.05). There was no significant difference in media area in the two groups.

These results suggest that (1) vitronectin-vitronectin receptor interaction mediates SMC migration in vivo, and (2) localized application of a vitronectin receptor antagonist to the arterial wall after balloon injury modifies this process and results in a significant reduction in the development of neointimal hyperplasia. Vitronectin-vitronectin receptor interaction may be an additional attractive target for pharmacologic manipulations aimed at limiting restenosis after vascular injury.

Get full access to this article

View all access options for this article.

References

McBride W. , Lange RA , Hillis LD : Restenosis after successful coronary angioplasty. N Eng J Med 318:1734-1737, 1988.

Clowes AW , Reidy MA , Clowes MM : Mechanisms of stenosis after arterial injury. Lab Invest 49:208-215, 1983.

Clowes AW , Clowes MM , Reidy MA : Kinetics of cellular proliferation after arterial injury. III. Endothelial and smooth muscle growth in chronically denuded vessels. Lab Invest 54:295-303, 1986.

Clowes AW , Clowes MM : Kinetics of cellular proliferation after arterial injury. IV. Heparin inhibits rat smooth muscle mitogenesis and migration. Circ Res 58:839-845, 1986.

Ross R. : The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 362:801-809, 1993.

Hynes RO : Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 69:11-25, 1992.

Clyman RI , McDonald KA , Kramer RH : Integrin receptors on aortic smooth muscle cells mediate adhesion to fibronectin, laminin, and collagen. Circ Res 67:175-186, 1990.

Brown SL , Lundgren CH , Nordt T. , et al: Stimulation of migration of human aortic smooth muscle cells by vitronectin: Implications for atherosclerosis. Cardiovasc Res 28:1815-1820, 1994.

Sawa H. , Lundgren C. , Sobel BE , et al: Increased intramural expression of plasminogen activator inhibitor type 1 after balloon injury: A potential progenitor of restenosis. J Am Coll Cardiol 24:1742-1748, 1994 .

10.

Smith JW , Cheresh DA : Integrin (αvβ3)-ligand interaction. Identification of a heterodimeric RGD binding site on the vitronectin receptor. J Biol Chem 265:2168-2172, 1990.

11.

Edelman ER , Simons M. , Sirois MG , et al: c-myc in vasculoproliferative disease. Circ Res 76:176-182, 1995.

12.

Sawa H. , Sobel BE , Fujii S. : Potentiation by hypercholesterolemia of the induction of aortic intramural synthesis of plasminogen activator inhibitor type 1 by endothelial injury . Circ Res 73:671-680, 1993.

13.

Sato R. , Komine Y. , Imanaka T. , et al: Monoclonal antibody EMR1a/212D recognizing site of deposition of extracellular lipid in atherosclerosis: Isolation and characterization of a cDNA clone for the antigen. J Biol Chem 265:21232-21236, 1990.

14.

Stadius ML , Rowan R. , Fleischhauer JF , et al: Time course and cellular characteristics of the iliac artery response to acute balloon injury. Arterioscler Thromb 12:1267-1273, 1992.

15.

Ferns GA , Raines E. , Sprugel KM , et al: Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 253:1129-1132, 1991.

16.

Choi ET , Engel L. , Callow AD , et al: Inhibition of neointimal hyperplasia by blocking α vβ3 integrin with a small peptide antagonist GpenGRGDSPCA. J Vasc Surg 19:125-134, 1994.

17.

Matsuno H. , Stassen JM , Vermylen J. , et al: Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation. Circulation 90:2203-2206, 1994.

18.

Bendeck MP , Irvin C. , Reidy MA : Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Circ Res 78:38-43, 1996.

A Vitronectin Receptor Antagonist Inhibits Neointimal Formation After Balloon Arterial Injury in Rabbits in Vivo

Abstract

Get full access to this article

References