Inducible nitric oxide synthase mediates the change from retinal to vitreal neovascularization in ischemic retinopathy
Florian Sennlaub, … , Yves Courtois, Olivier Goureau
Florian Sennlaub, … , Yves Courtois, Olivier Goureau
Published March 15, 2001
Citation Information: J Clin Invest. 2001;107(6):717-725. https://doi.org/10.1172/JCI10874.
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Article

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

Abstract

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.

Authors

Florian Sennlaub, Yves Courtois, Olivier Goureau

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Figure 2

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NOS isoform expression and NOS activity in the central P14 retina. iNOS ...
NOS isoform expression and NOS activity in the central P14 retina. iNOS is expressed in the inner nuclear layer (INL) of oxygen-incubated iNOS+/+ sections (a). Oxygen-exposed iNOS–/– (b) and room air–raised iNOS+/+ mice (c) do not show any positive cells. The signal on sections of oxygen-incubated iNOS+/+ mice is restricted to the INL of the central retina (d). Endothelial-cell staining on adjacent sections (e) reveals that this area corresponds precisely to the central ischemic area. NOS activity is detected by NADPH-diaphorase activity in the ganglion layer and nerve fiber layer on all sections, being slightly stronger in oxygen-incubated iNOS+/+ and iNOS–/– mice (f and g, respectively) compared with room air–raised iNOS+/+ mice (h), probably corresponding to nNOS expression (l–n). Room air–raised iNOS+/+ mice also exhibit a signal in a vessel-like distribution (h), probably corresponding to eNOS expression (k). Furthermore, we observe a signal in the central, ischemic retina of oxygen-incubated iNOS+/+ mice in the INL (f, arrowheads), This pattern corresponds to the expression pattern of iNOS in oxygen-incubated iNOS+/+ mice (a); neither eNOS (i) nor nNOS (l) expression is found in this distribution in oxygen-incubated iNOS+/+ mice, suggesting iNOS-specific activity. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; Ch, choroide; ON, optic nerve. Scale bar = 50 μm.