Arterial smooth muscle cell (SMC) proliferation contributes to a number of vascular pathologies. Prostaglandin E 2 (PGE 2 ), produced by the endothelium and by SMCs themselves, acts as a potent SMC growth inhibitor. The growth-inhibitory effects of PGE 2 are mediated through activation of G-protein-coupled membrane receptors, activation of adenylyl cyclases (ACs), formation of cAMP, and subsequent inhibition of mitogenic signal transduction pathways in SMCs. Of the 10 different mammalian AC

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... orms known today, seven isoforms (AC2-7 and AC9) are expressed in SMCs from various species. We show that, despite the presence of several different AC isoforms, the principal AC isoform activated by PGE 2 in human arterial SMCs is a calmodulin kinase II-inhibited AC with characteristics similar to those of AC3. AC3 is expressed in isolated human arterial SMCs and in intact aorta. We further show that arterial SMCs isolated from AC3-deficient mice are resistant to PGE 2 -induced growth inhibition. In summary, AC3 is the principal AC isoform activated by PGE 2 in arterial SMCs, and AC3 mediates the growth-inhibitory effects of PGE 2 . Because AC3 activity is inhibited by intracellular calcium through calmodulin kinase II, AC3 may serve as an important integrator of growth-inhibitory signals that stimulate cAMP formation and growth factors that increase intracellular calcium. Proliferation of arterial smooth muscle cells (SMCs) 1 contributes to several cardiovascular diseases such as atherosclerosis (1, 2). The intracellular second messenger cAMP markedly inhibits proliferation of SMCs and antagonizes growth factorstimulated activation of the extracellular signal-regulated kinase pathway and the S6 kinase 1 (S6K1) pathway and acti-