title: Inhibition of vascular smooth muscle cell proliferation by endothelium-dependent vasodilators.
abstract: This review considers the hypothesis that the endothelium-derived vasodilator agents, prostacyclin and nitric oxide, also function physiologically to inhibit vascular smooth muscle cell (VSMC) proliferation. The underlying biochemical mechanisms are also discussed. Prostacyclin and other agents that increase intracellular cAMP concentration are potent and effective inhibitors of the proliferation of isolated VSMC in culture. Such agents inhibit the initiation of proliferation in quiescent cells and the proliferation of logarithmically growing cells from a variety of sources, including man. The data implicate prostacyclin as an important regulator of VSMC proliferation, although there is little direct in vivo evidence. Nitric oxide-releasing drugs (and atriopeptins which increase intracellular cGMP concentration by a different mechanism) also inhibit proliferation of cultured VSMC. The effects are, however, partial and obtained at higher concentrations than those required for vasodilatation. Even allowing for the instability of the agents under tissue culture conditions, cGMP-elevating agents appear to be poorer at inhibiting proliferation than cAMP-elevating agents, despite similar or greater vasodilator potency. These data imply that nitric oxide is less likely than prostacyclin to be a physiological regulator of VSMC proliferation, although definitive experiments in vivo are again lacking. It also follows that nitrovasodilators are less attractive as therapy for VSMC proliferation than prostacyclin analogues or other cAMP-elevating agents, such as phosphodiesterase inhibitors. By analogy with the mechanisms of vasodilatation, inhibition of calcium mobilization and the subsequent activation of protein kinase C are considered as possible mechanisms underlying inhibition of proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Cardiology, University of Wales College of Medicine, Heath Park, Cardiff, Great Britain.
authors.forename: A C
authors.initials: AC
authors.lastname: Newby
authors.forename: K M
authors.initials: KM
authors.lastname: Southgate
authors.forename: J W
authors.initials: JW
authors.lastname: Assender
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D011464:Epoprostenol / Q000502:physiology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D011464:Epoprostenol; D000242:Cyclic AMP; D006152:Cyclic GMP