Abstract
Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine, specific D1-like agonists SKF 38393, and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration, proliferation, and hypertrophy were studied. We observed that cells stimulated by 5 ng/ml PDGF BB showed increased migration, proliferation and hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38393, or YM 435 at 1-10 μmol/l, and this prevention was reversed by Sch 23390 (1-10 μmol/l), a specific D1-like antagonist. These actions are mimicked by 1-10 μmol/l forskolin, a direct activator of adenylate cyclase and 8-bromo-cyclic AMP at 0.1-1 mmol/l. The actions are blocked by a specific protein kinase A (PKA) inhibitor N- [2- (p-bromocinnamylamino) ethyl] -5-isoquinoline-sulfonamide (H 89), but are not blocked by its negative control, N- [2- (N-formyl-p-chlorocinnamylamino) ethyl] -5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/ml) -mediated activation of phospholipase D (PLD), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration, proliferation and hypertrophy of VSMC, possibly through PKA activation and suppression of activated PLD, PKC and MAPK activity.
