TY - JOUR T1 - Pleiotropic Effects of YC-1 Selectively Inhibits Pathological Retinal Neovascularization and Promotes Physiological Revascularization in a Mouse Model of Oxygen-Induced Retinopathy JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.061366 SP - mol.109.061366 AU - Michael DeNiro AU - Ali Al-Halafi AU - Falah H Al-Mohanna AU - Osama AlSmadi AU - Futwan A Al-Mohanna Y1 - 2009/01/01 UR - http://molpharm.aspetjournals.org/content/early/2009/12/14/mol.109.061366.abstract N2 - VEGF and iNOS have been implicated in ischemia-induced retinal neovascularization. Retinal ischemia has been shown to induce VEGF and iNOS expression. It has been postulated that one of the crucial consequences of iNOS expression in the ischemic retina, is the inhibition of angiogenesis. Furthermore, iNOS was shown to be over-expressed in Muller cells from patients with diabetic retinopathy. YC-1, a small molecule inhibitor of HIF-1α, has been shown to inhibit iNOS expression in various tissue models. Our aim was to assess the pleiotropic effects of YC-1 in an OIR mouse model, and evaluate its therapeutic potential in HIF-1- and iNOS-mediated retinal pathologies. Dual-injections of YC-1 into the neovascular retinas decreased the total retinopathy score, inhibited vaso-obliteration and pathologic tuft formation, while concomitantly promoting physiological retinal revascularization, when compared with DMSO-treated group. Furthermore, YC-1-treated retinas exhibited a marked increase in immunoreactivities for CD31 and vWF, and displayed significant inhibition in HIF-1α protein expression. Furthermore, YC-1 down-regulated VEGF, EPO, ET-1, MMP-9, and iNOS message and protein levels. When hypoxic Muller and neuoroglial cells treated with YC-1, iNOS mRNA and protein levels were reduced in a dose-dependent fashion. We demonstrate that YC-1 inhibits pathological retinal neovascularization by exhibiting anti-neovascular activities, which impaired ischemia-induced expression of HIF-1 and its downstream angiogenic molecules. Furthermore, YC-1 enhanced physiological revascularization of the retinal vascular plexuses via the inhibition of iNOS mRNA and protein expressions. The pleiotropic effects of YC-1 allude to its possible use as a promising therapeutic iNOS inhibitor candidate for the treatment of retinal neovascularization.The American Society for Pharmacology and Experimental Therapeutics ER -