ADRENOMEDULLIN IS A POTENT INHIBITOR OF ANGIOTENSIN-II-INDUCED MIGRATION OF HUMAN CORONARY-ARTERY SMOOTH-MUSCLE CELLS

The migration of coronary artery medial smooth muscle cells (SMCs) int o the intima is proposed to be an important process of intimal thicken ing in coronary atherosclerotic lesions. In the current study, we exam ined the possible interaction of adrenomedullin, a novel vasorelaxant peptide, and angiotensin II (Ang II) on human coronary artery SMC migr ation using Boyden's chamber method. Ang II stimulated SMC migration i n a concentration-dependent manner between 10(-6) and 10(-8) mol/L. Th is stimulation was clearly blocked by the Ang II type 1 receptor antag onist losartan but not by the type 2 receptor antagonist PD 123319. Th e migration stimulatory effect of Ang II was chemotactic in nature for cultured human coronary artery SMCs but was not chemokinetic. Human a drenomedullin clearly inhibited Ang II-induced migration in a concentr ation-dependent manner. Human adrenomedullin stimulated cAMP formation in these cells. Inhibition by adrenomedullin of Ang II-induced SMC mi gration was paralleled by an increase in the cellular level of cAMP. 8 -Bromo-cAMP, a cAMP analogue, and forskolin, an activator of adenylate cyclase, inhibited the Ang II-induced SMC migration. These results su ggest that Ang II stimulates SMC migration via type 1 receptors in hum an coronary artery and adrenomedullin inhibits Ang II-induced migratio n at least partly through a cAMP-dependent mechanism. Taken together w ith the finding that adrenomedullin is synthesized in and secreted fro m vascular endothelial cells, this peptide may play a role as a local antimigration factor in certain pathological conditions.