دورية أكاديمية
أعرض في EDS

Endothelial HIF2α suppresses retinal angiogenesis in neonatal mice by upregulating NOTCH signaling.

التفاصيل البيبلوغرافية
العنوان: Endothelial HIF2α suppresses retinal angiogenesis in neonatal mice by upregulating NOTCH signaling.
المؤلفون: Duan LJ; Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA., Jiang Y; Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.; Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA., Fong GH; Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.; Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
المصدر: Development (Cambridge, England) [Development] 2024 Jun 01; Vol. 151 (11). Date of Electronic Publication: 2024 May 31.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Company Of Biologists Limited Country of Publication: England NLM ID: 8701744 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1477-9129 (Electronic) Linking ISSN: 09501991 NLM ISO Abbreviation: Development Subsets: MEDLINE
أسماء مطبوعة: Publication: Cambridge Eng : Company Of Biologists Limited
Original Publication: [Cambridge] : Company of Biologists, [c1987-
مواضيع طبية MeSH: 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, 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
مستخلص: 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.)
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معلومات مُعتمدة: R01 EY031593 United States EY NEI NIH HHS; 5R01EY031593 United States GF NIH HHS; 5R01EY031593 United States NH NIH HHS
فهرسة مساهمة: Keywords: DLL4; HIF2α; Hypoxia signaling; NOTCH; Prolyl hydroxylase; Retinal angiogenesis
المشرفين على المادة: 1B37H0967P (endothelial PAS domain-containing protein 1)
0 (Basic Helix-Loop-Helix Transcription Factors)
EC 1.14.11.29 (Egln1 protein, mouse)
0 (Receptors, Notch)
EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
0 (DLL4 protein, mouse)
0 (Adaptor Proteins, Signal Transducing)
0 (Vascular Endothelial Growth Factor A)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
0 (Calcium-Binding Proteins)
تواريخ الأحداث: Date Created: 20240521 Date Completed: 20240531 Latest Revision: 20240623
رمز التحديث: 20240623
مُعرف محوري في PubMed: PMC11190433
DOI: 10.1242/dev.202802
PMID: 38770916
قاعدة البيانات: MEDLINE
الوصف
تدمد:1477-9129
DOI:10.1242/dev.202802