The aim of this proposal is to apply cell and molecular biological techniques to examine the mechanisms responsible for endothelial and vascular smooth muscle cell migration in both an in vitro cell culture system that simulates wounding and in situ following experimental injury to the blood vessel intima. Vascular injury is associated with denudation of the endothelium, exposure of smooth muscle cells to blood elements, and deposition of platelets and monocytes at the site of injury. The vessel wall subsequently responds to this injury by migration of endothelial cells to repair the wound and migration of smooth muscle cells into the intima. In order to examine the pathophysiology present in the wounded vessel wall, the proposal will study the influence and mechanism of action of individual soluble platelet and monocyte factors on endothelial and smooth muscle cell migration. In particular, immunochemical, immunohistochemical, and molecular biological techniques will be employed to evaluate the role of vascular cell synthesis of extracellular matrix (ECM) components and alterations in cell associated proteolysis in mediating changes in endothelial and smooth muscle cell migration both in vitro with the different physiologic treatments and in situ. In order to directly evaluate the influence of alterations in levels of gene expression of these proteins on cell migration in vitro, endothelial and smooth muscle cells will be transfected with viruses containing specific protease, protease inhibitor, and extracellular matrix genes and subsequent changes in protein expression and migration kinetics will be examined. In addition, the proposal will examine the effect of antiplatelet therapy on vascular cell migration, deposition of platelet factors in the damaged vessel wall, and alterations in the ECM and protease profile of migrating vascular cells following experimental injury in situ. The results generated from this proposal will enhance the understanding of the role of changes in ECM synthesis and ECM proteolysis by migrating vascular cells in the causation of the pathophysiological changes observed in clinical cardiovascular disease.
| Madri, J A; Bell, L; Merwin, J R (1992) Modulation of vascular cell behavior by transforming growth factors beta. Mol Reprod Dev 32:121-6 |
| Bell, L; Luthringer, D J; Madri, J A et al. (1992) Autocrine angiotensin system regulation of bovine aortic endothelial cell migration and plasminogen activator involves modulation of proto-oncogene pp60c-src expression. J Clin Invest 89:315-20 |
| Madri, J A; Bell, L; Marx, M et al. (1991) Effects of soluble factors and extracellular matrix components on vascular cell behavior in vitro and in vivo: models of de-endothelialization and repair. J Cell Biochem 45:123-30 |
| Bell, L; Madri, J A (1990) Influence of the angiotensin system on endothelial and smooth muscle cell migration. Am J Pathol 137:7-12 |
