The phenotypic modulation of vascular smooth muscle cells (VSMCs) from the contractile (non-proliferating) to synthetic (proliferating) phenotype is thought to play an important role in atherogenesis. Although much attention has been given to the role of soluble growth factors in inducing smooth muscle cell proliferation, it has recently become clear that the synthetic VSMCs characteristic of the atherosclerotic lesions also have an abnormal extracellular matrix (ECM) and undergo changes in the expression of surface integrins. Based on our previous studies showing important cooperative effects of the ECM and mitogens in regulation of the cyclin-dependent kinases (cdks), we hypothesize that the changes in the ECM and integrins associated with synthetic SMCs may have an important role in controlling the proliferation of these cells in atherosclerosis. We also hypothesize that cell cycle progression of VSMCs is blocked in the normal aorta by release of growth inhibitory factors (PGI2, NO, and TGF-beta1) from endothelial cells, and that the decreased release of these factors at sites of turbulent flow plays an important role in the phenotypic modulation of local VSMCs from the contractile to synthetic from contractile to synthetic phenotype. This project tests these hypotheses in vivo and in vitro with four specific aims.
In aim 1, we will isolate aorta from atherosclerosis-prone mice (the LDLREdit knock-out mouse) and perform in situ analyses for (i) adhesion molecules, (ii) enzymes involve din No synthesis and PGI2 synthesis and action, and (iii) cyclin A. Particular attention will be pair to changes occurring prior to and in the early stages of lesions development.
In aims 2 and 3, we will use early passage VSMC cultures from normal mice to determine the degree to which cell adhesion, and distinct ECM proteins and their integrins regulate the PI phase cyclins and cdk inhibitors.
In aim 4, we will determine the mechanism by which endothelial cell growth inhibitors influence growth factor and/or ECM dependent cell cycle progression of VSMCs. Overall, results from these studies will define the role of the ECM as a cell regulatory element controlling VSMC proliferation and determine whether changes in the local release of endothelial cell- derived inhibitors can account for the discrete nature of VSMC proliferation and lesion development in atherosclerosis.
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