Blockade of nitric-oxide synthase reduces choroidal neovascularization.
Nitric oxide (NO) promotes retinal and choroidal neovascularization, although different isoforms of nitric-oxide synthetase (NOS) are critical in each. Deficiency of endothelial NOS (eNOS) suppresses retinal but not choroidal neovascularization, whereas deficiency of neuronal NOS (nNOS) or inducible NOS (iNOS) suppresses choroidal, but not retinal neovascularization. In this study, we investigated the effect of N(G)-monomethyl-L-arginine (L-NMMA), a nonspecific NOS inhibitor, in three models of ocular neovascularization. Oral administration of L-NMMA caused significant inhibition of choroidal neovascularization in mice with laser-induced rupture of Bruch's membrane and significantly inhibited subretinal neovascularization in transgenic mice with expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF mice) but did not inhibit retinal neovascularization in mice with ischemic retinopathy. By extensive mating among mice deficient in NOS isoforms, triple homozygous mutant mice deficient in all three NOS isoforms were produced. These mice had marked suppression of choroidal neovascularization at sites of rupture of Bruch's membrane and near-complete suppression of subretinal neovascularization in rho/VEGF mice but showed no difference in ischemia-induced retinal neovascularization compared with wild-type mice. These data indicate that NO is an important stimulator of choroidal neovascularization and that reduction of NO by pharmacologic or genetic means is a good treatment strategy. However, the situation is more complex for ischemia-induced retinal neovascularization for which NO produced in endothelial cells by eNOS is stimulatory, but NO produced in other retinal cells by iNOS and/or nNOS is inhibitory. Selective inhibitors of eNOS may be needed for treatment of retinal neovascularization.
Ando
Akira
A
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Yang
Amy
A
Nambu
Hiroyuki
H
Campochiaro
Peter A
PA
D000818:Animals; D016570:Bruch Membrane / Q000293:injuries; D020256:Choroidal Neovascularization / Q000517:prevention & control*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007511:Ischemia / Q000150:complications; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019323:omega-N-Methylarginine / Q000627:therapeutic use*
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase