Hypertension and atherosclerosis are caused by the action of vasoactive agents and mitogens upon vascular smooth muscle cells or by abnormal responses of these cells. Vasoactive agents and mitogens act by inducing a variety of enzymatic processes and ion transport events within the cell like phospholipase C and protein kinase C activity, Ca2+ transport, and Na+/H+ exchange. Signal transducers (typically GTP-binding, or G, proteins) couple occupation of the receptor to these enzymatic or ion transport activities. Work thus far shows that some of the signaling processes and intracellular events induced by vasoactive agents and mitogens are similar. In fact, little is known about what distinguishes the cellular response to a vasoconstrictor like angiotensin II from a mitogen like platelet derived growth factor or why a clotting factor like thrombin can become a mitogen after prolonged stimulation of the cell. One possibility is that under physiologic conditions, the cell is protected from mitogenic activity by growth inhibitors. This grant proposes to look for differences in the immediate responses to vasoactive substances and mitogens, to ask about the role of G proteins after prolonged hormonal stimulation, and to examine the mechanism(s) of action of growth inhibitors. The techniques to be used include cell culture of vascular smooth muscle cells, measurements of intracellular pH and Ca2+, assay of phospholipase C and A2 and of protein kinase C, assay of mitogenesis, and introduction of GTP analogues and antibodies into cells by transient permeabilization and/or microinjection. Results from the proposed studies will provide new insights into the distinct responses of vascular smooth muscle cells to vasoactive agents, mitogens and growth inhibitors. Understanding the normal responses of these cells is critical to understanding the deranged function seen in hypertension and atherosclerosis.
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