One of the widely studied mechanisms involved in the development and maintenance of hypertension is the renin-angiotensin system. The potent vasoconstrictor peptide angiotensin II (AII) which plays an important role in cardiovascular regulation, fluid homeostasis and neuroendocrine regulation has been shown to act as a cellular growth factor, exerting hypertrophic and mitogenic effects on VSM cells. It is becoming increasingly evident that VSM cell growth is an important feature contributing to the increase in vascular resistance. Both hyperinsulinemia and insulin resistance have been claimed to predispose increased vascular tone, and therefore, hyperinsulinemia may play a role in the development of structural changes in the vessel wall spontaneously hypertensive rat (SHR) and it is of interest to determine whether hyperinsulinemia is involved in the hypersensitivity of VSM in SHR. AII receptor subtypes, AT1 and AT2 have been identified and characterized and it was shown that AT1 receptors mediate AII responses in the vasculature. We plan to characterize the AT1 receptors in prehypertensive (4-6 week-old) and established hypertensive (12 week-old) age-matched SHR, and its normotensive control, Wistar-Kyoto (WKY) rat. We have demonstrated that insulin up-regulates AII-receptors and believe that it play a role in AII-stimulated growth of VSM cells. We plan to determine whether protein tyrosine kinase phosphorylation which is suggested to be the mechanisms by which vascular smooth muscle (VSM) cell growth is stimulated, is essential for the signal transduction of AII-stimulated growth of VSM cells, and to determine the role of insulin in the regulation of AT1 receptors. The studies will involve receptor binding assays, the measurement of: the expression of AT1 receptor mRNA, receptor coupling mechanisms including IP3 production, PKC activity and intracellular Ca2+ release, AII-stimulated tyrosine kinase phosphorylation, c-fos, c-myc, and c-jun expression and DNA synthesis in VSM cells. Also, the effect of insulin of the gene promoter activity and the mRNA stability of AT1-receptor will be determined. Finally, a study will be done to see whether the up-regulation of AT1-receptors by insulin is coupled to the mechanisms mentioned above. We hope to gain some insight into the mechanisms of hypersensitivity of VSM which may be involved in the etiology of essential hypertension.
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