1. Endothelial HIF2α suppresses retinal angiogenesis in neonatal mice by upregulating NOTCH signaling.
- Author
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Duan LJ, Jiang Y, and Fong GH
- Subjects
- Animals, Mice, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing genetics, Retina metabolism, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Calcium-Binding Proteins metabolism, Calcium-Binding Proteins genetics, Retinal Vessels metabolism, Angiogenesis, Signal Transduction, Basic Helix-Loop-Helix Transcription Factors metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Receptors, Notch metabolism, Receptors, Notch genetics, Up-Regulation, Hypoxia-Inducible Factor-Proline Dioxygenases metabolism, Hypoxia-Inducible Factor-Proline Dioxygenases genetics, Retinal Neovascularization metabolism, Retinal Neovascularization genetics, Retinal Neovascularization pathology, Animals, Newborn, Endothelial Cells metabolism
- Abstract
Prolyl hydroxylase domain (PHD) proteins are oxygen sensors that use intracellular oxygen as a substrate to hydroxylate hypoxia-inducible factor (HIF) α proteins, routing them for polyubiquitylation and proteasomal degradation. Typically, HIFα accumulation in hypoxic or PHD-deficient tissues leads to upregulated angiogenesis. Here, we report unexpected retinal phenotypes associated with endothelial cell (EC)-specific gene targeting of Phd2 (Egln1) and Hif2alpha (Epas1). EC-specific Phd2 disruption suppressed retinal angiogenesis, despite HIFα accumulation and VEGFA upregulation. Suppressed retinal angiogenesis was observed both in development and in the oxygen-induced retinopathy (OIR) model. On the other hand, EC-specific deletion of Hif1alpha (Hif1a), Hif2alpha, or both did not affect retinal vascular morphogenesis. Strikingly, retinal angiogenesis appeared normal in mice double-deficient for endothelial PHD2 and HIF2α. In PHD2-deficient retinal vasculature, delta-like 4 (DLL4, a NOTCH ligand) and HEY2 (a NOTCH target) were upregulated by HIF2α-dependent mechanisms. Inhibition of NOTCH signaling by a chemical inhibitor or DLL4 antibody partially rescued retinal angiogenesis. Taken together, our data demonstrate that HIF2α accumulation in retinal ECs inhibits rather than stimulates retinal angiogenesis, in part by upregulating DLL4 expression and NOTCH signaling., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)
- Published
- 2024
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