Impacts of hypoxia-inducible factor-1 knockout in the retinal pigment epithelium on choroidal neovascularization.
OBJECTIVE
Hypoxia-inducible factor (HIF)-1 is a key oxygen sensor and is believed to play an important role in neovascularization (NV). The purpose of this study is to determine the role of retinal pigment epithelium (RPE)-derived HIF-1α on ocular NV.


METHODS
Conditional HIF-1α knockout (KO) mice were generated by crossing transgenic mice expressing Cre in the RPE with HIF-1α floxed mice, confirmed by immunohistochemistry, Western blot analysis, and fundus fluorescein angiography. The mice were used for the oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models.


RESULTS
HIF-1α levels were significantly decreased in the RPE layer of ocular sections and in primary RPE cells from the HIF-1α KO mice. Under normal conditions, the HIF-1α KO mice exhibited no apparent abnormalities in retinal histology or visual function as shown by light microscopy and electroretinogram recording, respectively. The HIF-1α KO mice with OIR showed no significant difference from the wild-type (WT) mice in retinal levels of HIF-1α and VEGF as well as in the number of preretinal neovascular cells. In the laser-induced CNV model, however, the disruption of HIF-1α in the RPE attenuated the over expression of VEGF and the intercellular adhesion molecule 1 (ICAM-1), and reduced vascular leakage and CNV area.


CONCLUSIONS
RPE-derived HIF-1α plays a key role in CNV, but not in ischemia-induced retinal NV.
Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Mingkai
M
Lin
Yang
Y
Hu
Ying
Y
Chen
Kevin K
KK
Zhou
Ji
J
Jin
Meili
M
Zhu
Yun-Zheng
YZ
Le
Jian
J
Ge
Jian-Xing
JX
Ma
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000378:metabolism*; D004195:Disease Models, Animal; D004596:Electroretinography; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction / Q000379:methods; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A