This proposal focuses on the role of the Ca2+ inhibited adenylyl cyclase (AC3) in the regulation of vascular smooth muscle (VSM) proliferation and smooth muscle contraction. cAMP is anti-proliferative for VSM and it antagonizes the actions of mitogens that stimulate proliferation through activation of the Erk/MAP kinase pathway. Furthermore, cAMP mediates relaxation of VSM caused by '-2-adrenergic agonists and counteracts vasoconstriction caused by a -1-adrenergic agonists. We hypothesize that Ca2+ inhibition of AC3 plays a major role in both processes by releaving the cAMP c check on proliferation and smooth muscle constriction. AC3 is strongly stimulated by Gs-coupled receptors including '-adrenergic receptors and it is inhibited by Ca2+. Ca2+ inhibition is mediated by CaM kinase II (CaMKII) which phosphorylates AC3 at Ser-1076. To explore the role of AC3 for VSM function we disrupted the AC3 gene in mice. The objectives of this proposal are to determine if Ca2+ inhibits the activity of AC3 in VSM by stimulating the phosphorylation of AC3 at Ser-1076, to determine if proliferation of cultured VSM cells from AC3 mutant mice is enhanced is enhanced compared to wild type mice, and to determine if proliferation of cultured VSM cells is reduced in CaMKII mutant mice. In addition, we propose to examine cardiodynamic parameters in AC3 mutant and CaMKII mutant mice. These studies should provide fundamental insight concerning the regulation of VSM functions by mitogens and adrenergic agents.
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