HYPOXIC RESPONSES OF VASCULAR SMOOTH MUSCLE

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Regulation of vascular tone involves the close interaction between endothelial and smooth muscle cells in the vessel wall. Abnormal vessel tone and structure underlie the pathophysiology of such important diseases as pulmonary hypertension and atherosclerosis. Hypoxia may play an important role in the pathogenesis of pulmonary hypertension by activating the expression of specific genes in human vascular endothelial cells resulting in the elaboration of protein products able to induce vasoconstriction, smooth muscle cell hyperplasia, and matrix remodeling. In addition, their recent studies show that hypoxia has direct effects on the smooth muscle cells (SMC), which in turn, can release mediators that regulate gene expression in the endothelial cells (EC). Vascular SMC cultured in a hypoxic environment demonstrated a seven-fold increase in the expression of the heme oxygenases-p1 (NO-1) mRNA and protein. HO catalyzes the breakdown of heme to yield carbon monoxide (CO) and biliverdin. Like NO, CO is a molecule that activates quanylate cyclase resulting in elevated cGMP levels. Increased CGMP levels in the vasculature causes SMC relaxation. It is hypothesized that SMC-derived CO is a regulator of vascular tone under physiologic and pathophysiologic (such s hypoxic) conditions, SMC-derived CD can increase intracellular cGMP levels in an autocrine manner or it can regulate the expression of potent vasoactive mediators produced by E C such as endothelin and PDGF which then control SMC growth in a paracrine manner. The aims of this proposal are: To study the physiologic role of CO on EC and SMC function under normoxic and hypoxic conditions, and to examine molecular mechanisms controlling HO-gene expression in hypoxic vascular SMC. The long-term expectation is the an understanding of hypoxic vascular SMC. The long-term expectation is that an understanding of the basic molecualr mechanisms responsible for control vascular tone will load to new therapies to enhance the body a adaptive response s to hypoxia.