부산대학교 도서관

Introduction: Peripheral arterial disease (PAD) is an important cause of morbidity and mortality with little effective treatment currently available. Occlusive atherosclerosis in lower limbs occurs as a last step of endothelial nitric oxide (NO) deficiency limiting signal transduction necessary for normal vascular function. Thus, delivery of NO appears to be an attractive therapeutic option in several cardiovascular conditions.Hypothesis: We hypothesized that the NO-donor MPC-1011 might elicit vasodilation, angiogenesis and arteriogenesis and in turn improve limb perfusion, in a hindlimb ischemia model.Methods: Hindlimb ischemia was induced by femoral artery ligation in rats which were randomized to receive placebo, MPC-1011, cilostazol or both, for up to 28 days. Blood flow was assessed by laser Doppler imaging, angiogenesis and arteriogenesis by immunohistochemistry post mortem, and tissue VEGF, SDF-1 and cGMP levels by ELISA.Results: After femoral artery occlusion, limb perfusion in rats receiving either MPC-1011 alone or in combination with cilostazol was increased throughout the treatment regimen (P<0.05). Capillary density and the number of arterioles was increased only with MPC-1011 (+24.6% and +28.7%, vs placebo and cilostazol, resp.; P<0.05). MPC-1011 improved vascular remodeling by increasing luminal diameter in the ischemic limb (+23.1% and +27.0%, vs placebo and cilostazol, resp.; P<0.05). Moreover, MPC-1011 stimulated the release of proangiogenic cytokines, including VEGF (+42.2% vs placebo; P<0.05), SDF-1 alpha (+30.7% vs placebo; P<0.05) and increased tissue cGMP levels (+60.2% vs placebo; P<0.05), potentiated proliferation and migration of endothelial cells, which was blunted in the presence of soluble guanylyl cyclase inhibitor LY83583. In MPC-1011-treated rats Lin/CD31/CXCR4 cells were increased by 92% and Lin/VEGFR2/CXCR4 cells by 76.8% vs placebo (P<0.05).Conclusions: Here we show for the first time that the NO donor, MPC-1011, is a potent and specific promoter of angiogenesis and arteriogenesis in a hindlimb ischemia model in a NO-cGMP-VEGF-dependent manner. This sets the basis to evaluate and confirm the efficacy of such therapy in a clinical setting in patients with PAD and impaired limb perfusion.