While the aorta and other large arteries hypertrophy in hypertension, peripheral vascular resistance is increased by remodeling of arterioles and small arteries into vessels with smaller lumens, independently of changes in wall cross-sectional area. The goal of this research proposal is to test the overall hypothesis that arteriolar remodeling consists of an adjustment of smooth muscle cells and wall matrix components to chronic vasoconstriction using a three stage approach. First, scanning and transmission electron microscopy will be used to determine resting length of smooth muscle cells and percent of wall occupied by endothelium, collagen, basement membrane, and smooth muscle in one-kidney, one-clip (lKlC) hypertensive rats. Second, the hypothesis that chronic vasoconstriction precedes remodeling will be tested by measuring arteriolar tone in the spinotrapezius muscle of lKlC rats and the hypothesis that elevated pressure is a necessary stimulus for remodeling will be tested in experiments on aortic coarctation. Third, the molecular basis of hypertrophy and remodeling will be studied using in situ hybridization for mRNA of growth factors and matrix proteins in aortas and arterioles. This technique will be applied first to the model of 14-day infusion of subpressor doses of angiotensin II because of its possible role in renal hypertension and its effect on specific growth factors as suggested by experiments on cultured cells. Aortas and arterioles will be probed for mRNA for bFGF, TGF-beta, PDGF-A-chain, alpha-actin, collagen and laminin. Image analysis will be used to quantify the in situ hybridization signal. The hypothesis that turnover of smooth muscle cells occurs during remodeling will be tested by immunocytochemistry for proliferating cell nuclear antigen (cyclin). These techniques will then be applied to vessels from lKlC hypertensive rats. Results will allow the linkage of structural changes to specific gene expression localized to a cell type, i.e., endothelial cells or smooth muscle cells. Comparisons of results in the aorta and arterioles may indicate why the former hypertrophies while the latter remodels. Thus these studies will further delineate the role of individual growth factors suggested from in vitro experiments and reveal paracrine relationships between cell types that form the basis of arteriolar remodeling and increased vascular resistance in hypertension.
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