Endothelium-specific deletion of Nox4 delays retinal vascular development and mitigates pathological angiogenesis
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ORIGINAL PAPER
Endothelium‑specific deletion of Nox4 delays retinal vascular development and mitigates pathological angiogenesis Xixiang Tang1,2,3,4 · Joshua J. Wang1,2 · Jinli Wang1,2 · Hanna E. Abboud5 · Yanming Chen3 · Sarah X. Zhang1,2,6 Received: 19 June 2020 / Accepted: 6 November 2020 © Springer Nature B.V. 2020
Abstract NADPH oxidase 4 (Nox4) is a major isoform of NADPH oxidases playing an important role in many biological processes. Previously we have shown that Nox4 is highly expressed in retinal blood vessels and is upregulated in oxygen-induced retinopathy (OIR). However, the exact role of endothelial Nox4 in retinal angiogenesis remains elusive. Herein, using endothelial cell (EC)-specific Nox4 knockout (Nox4EC−KO) mice, we investigated the impact of endothelial Nox4 deletion on retinal vascular development and pathological angiogenesis during OIR. Our results show that deletion of Nox4 in ECs led to retarded retinal vasculature development with fewer, blunted-end tip cells and sparser, dysmorphic filopodia at vascular front, and reduced density of vascular network in superficial, deep, and intermediate layers in postnatal day 7 (P7), P12, and P17 retinas, respectively. In OIR, loss of endothelial Nox4 had no effect on hyperoxia-induced retinal vaso-obliteration at P9 but significantly reduced aberrant retinal neovascularization at P17 and decreased the deep layer capillary density at P25. Ex vivo study confirmed that lack of Nox4 in ECs impaired vascular sprouting. Mechanistically, loss of Nox4 significantly reduced expression of VEGF, p-VEGFR2, integrin αV, angiopoietin-2, and p-ERK1/2, attenuating EC migration and proliferation. Taken together, our results indicate that endothelial Nox4 is important for retinal vascular development and contributes to pathological angiogenesis, likely through regulation of VEGF/VEGFR2 and angiopoietin-2/integrin αV/ERK pathways. In addition, our study suggests that endothelial Nox4 appears to be essential for intraretinal revascularization after hypoxia. These findings call for caution on targeting endothelial Nox4 in ischemic/hypoxic retinal diseases. Keywords Nox4 · Retina · Endothelial cells · Angiogenesis · Development · Vascularization
Introduction
Hanna E. Abboud: Deceased. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09757-3) contains supplementary material, which is available to authorized users. * Sarah X. Zhang [email protected] 1
Department of Ophthalmology and Ross Eye Institute, University at Buffalo, State University of New York, Buffalo, NY, USA
2
SUNY Eye Institute, State University of New York, New York, NY, USA
3
Department of Endocrinology and Metabolism, The Third Affiliated Hospital, Sun Yat-Sen University; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China
Angiogenesis is a fundamental biological process involved in normal physiology of development and tissue repair; however, uncontrolled and dysregulated angiogenesis contributes to the path
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