We have begun to understand the pharmacology of molecules controlling proliferative responses of a single vessel; the carotid artery of the rat following balloon angioplasty. This process begins with disruption of medial smooth muscle cells and release of FGF. Later events are controlled by PDGF, the renin-angiotensin system, catecholamines, and other growth factors. The present study will determine whether similar molecules control smooth muscle replicative responses in renal microvessels undergoing disruptive injury in response to a dramatic rise in blood pressure. We are equally interested in understanding proliferative responses that occur with less severe modes of injury to the vessel wall. It is likely, for example, that different forms of injury occur at different levels of the vascular tree and, therefore, different mechanisms may control smooth muscle proliferative responses. Proliferation, moreover, is only part of the response to injury. Studies in the carotid artery have revealed a unique set of genes, the """"""""pi"""""""" genes, which characterize smooth muscle cells responding to injury. These proteins have potentially important roles in the vascular pathology. We will study the patterns of gene expression in renal microvascular smooth muscle responding to injury to examine the effects of therapies designed to alter patterns of gene expression. Finally, we want to know how proliferation relates to changes in vessel wall mass that regulate vascular resistance. All of this data on the pharmacology of smooth muscle replicative responses following hyper- tensive injury needs to be placed in a context in the important search for site of injury that may be critical in determining the effects of hypertension on the kidney as well as identifying sites that may themselves lead to a more permanent elevation in pressure. Therefore, critical aspects of these studies include analyses of the specific sites of injury as well as the long-term ability of those sites to repair themselves.
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