DOPAMINE AS A NOVEL ANTIMIGRATION AND ANTIPROLIFERATIVE FACTOR OF VASCULAR SMOOTH-MUSCLE CELLS THROUGH DOPAMINE D1-LIKE RECEPTORS

Vascular smooth muscle cell (VSMC) migration and proliferation are bel ieved to play key roles in atherosclerosis. To elucidate the role of v ascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine and specific D1-like agonists SKF 38393 and YM 435 on platele t-derived growth factor (PDGF) BE-mediated VSMC migration and prolifer ation were studied. We observed that cells stimulated by PDGF-BB (5 ng /mL), showed increased migration and proliferation. These effects were prevented by coincubation with dopamine, SKF 38393, or YM 435 (1 to 1 0 mu mol/L), and this prevention was reversed by Sch 23390 (1 to 10 mu mol/l), a specific D1-like antagonist. These actions are mimicked by forskolin (1 to 10 mu mol/L), a direct activator of adenylate cyclase and 8-bromo-cAMP at 0.1 to 1 mmol/L and are blocked by a specific prot ein kinase A inhibitor, mocin-namylamino)ethyl]-5-isoquinoline-sulfona mide (H 89), but not blocked by its negative control, rmyl)-p-chloroci annamylamino)ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/m L)-mediated activation of phospholipase D, protein kinase C, and mitog en activated protein kinase activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-lik e receptor agonists inhibit migration and proliferation of VSMC, possi bly through protein kinase A activation and suppression of activated p hospholipase D, protein kinase C, and mitogen-activated protein kinase activity.