The objectives of this program project are to characterize the mechanisms that control growth and development and regulate contractile, synthetic and secretory functions in vascular smooth muscle. Several levels of regulation will be explored in integrated, multidisciplinary projects. One level is regulation of gene expression, growth and development, with a new emphasis on cell and molecular biological approaches (Projects 2, 4, 7 and 8). The next level is receptor function and regulation of myoplasmic [Ca2], inositol phospholipids and other second messengers (Projects 3, 5, 6, 7 and 8). The third level is regulation of crossbridge interactions and the mechanism of chemomechanical transduction leading to contraction and changes in vascular resistance (Projects 1, 3, 6 and 8). Fifteen faculty members from the Departments of Anesthesiology, Medicine (Divisions of Cardiology and Endocrinology) , Pathology, Pediatrics, Pharmacology and Physiology are collaborating in 8 projects focused on : (1) regulation of crossbridge interactions; (2) regulation of hypertrophic and hyperplastic growth; (3) regulation of tone and microvessel resistance; (4) regulation of receptor gene expression; (5) regulation of myoplasmic (Ca2+) by inositol phosphates; (6) regulation of signal- and chemomechanical- transduction; (7) regulation of renin/angiotensin biosynthesis, storage and secretion at renal juxtaglomerular and other vascular smooth muscle cells; and (8) regulation of angiotensin receptors, signal transduction, and endothelium-vascular smooth muscle cell interactions. Several common experimental preparations are emphasized including various smooth muscle, fibroblast, and endothelial cell preparations supplied and characterized by the Cell Culture Core Laboratory. An Electron Microscopy and Histochemistry Core supports most of the projects. The research program will provide basic information on the properties and function of vascular smooth muscle relevant to an understanding of diseases such as hypertension, atherosclerosis and vasospasm, and to the development of therapeutic approaches for their treatment.
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