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

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.

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