More than 3 million procedures (eg angioplasty) are performed each year to open blocked arteries. Unfortunately, one in three will fail in the short term from recurrent blockage at the site of repair, termed restenosis. Restenosis has traditionally been attributed to the accumulation of smooth muscle cells and their extracellular matrix at sites of injury. More recently, shrinkage of the artery wall as it heals (inward or constrictive remodeling) has been found to contribute more to lumen narrowing after angioplasty than new wall mass per se. The cellular and molecular basis of remodeling is poorly defined. This the broad objectives of the research program are to define mechanisms driving constrictive remodeling after angioplasty. HA is a large glycoaminoglycan prominent in matrix deposited at sites of angioplasty and remodeling. HA is known to enhance collagen reorganization by fibroblasts in wounds and to speed wound closure, prompting the focus of the research on collagen-HA interactions in the injured artery wall. HA receptors are important for arterial smooth muscle cell growth and migration in vitro. Contraction of collagen is enhanced in the presence of HA and limited by blocking HA receptors. Fragments of HA have been developed to block HA-receptors and inhibit intimal hyperplasia in rats and rabbits. Collagen and HA are prominent components of the healing response after angioplasty in atherosclerotic arteries and the PI's studies suggest that the mechanism of wall shrinkage is collagen reorganization by smooth muscle cells and adventitial fibroblasts. This proposal aims to employ HA-receptor knockout mice to study the role of these receptors in smooth muscle cells contraction of collagen gels in vitro and the impact of HA-receptor deletions on carotid artery constrictive remodeling in vivo. A unique model of angioplasty in atherosclerotic monkeys will also be used to test the hypothesis that a non selective HA receptor antagonist infused for 4 weeks will inhibit artery wall constriction and restenosis. Separate studies will explore the gene expression patterns induced during constrictive remodeling by applying RNA from arteries after injury, and from smooth muscle cells contracting collagen in vitro, to human gene arrays.
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