Inducible nitric oxide synthase mediates the change from retinal to vitreal neovascularization in ischemic retinopathy

J Clin Invest. 2001 Mar;107(6):717-25. doi: 10.1172/JCI10874.


Intravitreal neovascular diseases are a major cause of blindness worldwide. It remains unclear why neovessels in many retinal diseases spread into the physiologically nonvascularized vitreous rather than into the ischemic retinal areas, where the angiogenic factors are released. Here we show that inducible nitric oxide synthase (iNOS) is expressed in the ischemic retina. Using iNOS knockout mice and the iNOS inhibitor 1400W, we demonstrate that iNOS expression inhibits angiogenesis locally in the avascular retina, mediated at least in part by a downregulation of VEGF receptor 2 (VEGFR2) in cells adjacent to iNOS-expressing cells. At the same time, pathological intravitreal neovascularization is considerably stronger in iNOS-expressing animals. These findings demonstrate that iNOS plays a crucial role in retinal neovascular disease and show that it offers an ideal target for the control of vitreal neovascularization through improvement of the vascularization of the hypoxic retina.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • DNA Primers / genetics
  • Disease Models, Animal
  • Humans
  • Ischemia / enzymology*
  • Ischemia / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic*
  • Nitric Oxide Synthase / deficiency
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / physiology*
  • Nitric Oxide Synthase Type II
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Retina / enzymology*
  • Retina / pathology
  • Retinal Vessels / enzymology*
  • Retinal Vessels / pathology
  • Vitreous Body / blood supply*
  • Vitreous Body / enzymology*


  • DNA Primers
  • RNA, Messenger
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse