Nitric oxide synthases in vascular cells

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Thrombin prevents the expression of inducible nitric oxide synthase in vascular smooth muscle cells by a proteolytically-activated thrombin receptor

Proteolytically active forms of thrombin (α- and γ-thrombin) and thrombin receptor peptides inhibited the release of nitrite, a stable endproduct of nitric oxide, evoked by interleukin-1 β (IL-1 β) in cultured vascular smooth muscle cells while proteolytically inactive forms [D-Phe-Pro-Arg chloromethyl ketone-α-thrombin (PPACK-α-thrombin) and diisopropylphosphoryl-α-thrombin (DIP-α-thrombin)] had either no or only minimal inhibitory effects. Under bioassay conditions, perfusates from columns containing IL-1 β-activated vascular smooth muscle cells or cells treated with IL-1 β plus PPACK-α-thrombin relaxed detector blood vessels. These relaxations were abolished by the inhibitor of nitric oxide synthesis, N(G)-nitro-L-arginine. No relaxations were obtained with untreated cells or IL-1 β-treated cells in the presence of α-thrombin. The expression of inducible nitric oxide synthase mRNA and protein in vascular smooth muscle cells by IL-1 β was impaired by α-thrombin. These results demonstrate that thrombin regulates the expression of the inducible nitric oxide synthase at a transcriptional level via the proteolytic activation of the thrombin receptor in vascular smooth muscle cells.link_to_subscribed_fulltex

Red wine polyphenols prevent acceleration of neovascularization by angiotensin II in the ischemic rat hindlimb

Studies in both animals and humans indicate that angiogenesis is implicated in the development of atherosclerotic lesions. Thus, inhibition of angiogenesis may provide a novel therapeutic approach for the treatment of atherosclerosis. Because epidemiological studies have indicated an inverse relation between red wine intake and coronary disease, we determined the antiangiogenic potential of red wine polyphenols (RWPs) in the ischemic hindlimb model. Neovascularization was accelerated by the chronic infusion of angiotensin II (Ang II; 0.1 mg/ kg/day). RWPs (25 mg/kg/day) or vehicle were administrated in the drinking water 7 days before the ligation. After 21 days, Ang II potentiated the ischemia-induced neovascularization in the hindlimb, as assessed by microangiography and measurement of microvessel density. This effect was associated with an increased formation of reactive oxygen species (ROS) and increased expression of hypoxia-inducible factor (HIF)-2α, endothelial nitric-oxide synthase (eNOS), and vascular endothelial growth factor (VEGF). RWPs intake significantly prevented the angiogenic process, the formation of ROS and nitrated proteins, and the expression HIF-2α, eNOS, and VEGF induced by Ang II. Similar preventive effects were observed with the antioxidant and NADPH oxidase inhibitor apocynin. These findings indicate that RWPs have potent antiangiogenic properties in vivo by preventing the expression of proangiogenic factors, including VEGF and eNOS most likely by inhibiting oxidative stress. Thus, the antiangiogenic properties of red wine polyphenols might contribute to their protective effect against coronary disease. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.link_to_OA_fulltex