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Kelu Zhou, Mingkai Lin, Sr.; The Role Of Retinal Pigment Epithelium (rpe)-dirived Hypoxia-inducible Factor-1 In Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1803.
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Choroidal neovascularizaiton (CNV) is associated with defects in Bruch's membrane and excessive expression of vascular endothelial growth factor (VEGF). CNV is related to multiple retinal vascular diseases and is one of the most common causes of severe vision loss, However, its pathogenesis is still poorly understood. Hypoxia-inducible factor (HIF)-1α has been shown to be a master regulator for ischemia-induced neovascularization (NV). The purpose of this study is to determine the role of HIF-1 expressed in RPE cells in the laser-induced CNV using RPE cell-specific conditional HIF-1α knockout (KO) mice.
The HIF-1α conditional KO mice were generated by crossing the RPE specific Cre transgenic mice with the HIF-1α floxed mice. Electroretinography (ERG) examination was performed to diagnose the visual function under normal conditions. CNV was induced by laser photocoagulation in the HIF-1α-/- mice, while the HIF-1α+/+ littermates served as controls. Expression of HIF-1α and pro-angiogenic factors were measured by Western blot analysis. Fundus fluorescein angiography was performed to evaluate the leakage of CNV. The size of CNV lesion was measured on RPE-choroid flat mounts.
The HIF-1α-/- mice showed significantly decreased HIF-1α levels in the RPE, while did not manifest any detectable histological or visual functional abnormalities under normal conditions, compared to the HIF-1α+/+ mice. In the CNV model, the HIF-1α-/- mice showed attenuated over-expression of HIF-1α, VEGF and ICAM-1 in the eyecup (retina/choroid), compared to the HIF-1α+/+ CNV controls. Fluorescein angiography demonstrated that RPE-specific HIF-1α KO alleviated retinal vascular leakage in laser induced CNV model. In addition, significantly smaller CNV lesions were observed in the HIF-1α-/- mice than in the HIF-1α+/+ littermates.
HIF-1α deficiency in the RPE under normal condition does not affect vision. HIF-1α expressed in RPE cells plays a key role in mediating CNV, suggesting that targeting HIF-1α in RPE cells is a promising therapeutic strategy for retinal vascular diseases with CNV.
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