title: Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina.
abstract: Vascular/parenchymal crosstalk is increasingly recognized as important in the development and maintenance of healthy vascularized tissues. The retina is an excellent model in which to study the role of cell type-specific contributions to the process of blood vessel and neuronal growth. During retinal vascular development, glial cells such as astrocytes provide the template over which endothelial cells migrate to form the retinal vascular network, and hypoxia-regulated vascular endothelial growth factor (VEGF) has been demonstrated to play a critical role in this process as well as pathological neovascularization. To investigate the nature of cell-specific contributions to this process, we deleted VEGF and its upstream regulators, the hypoxia-inducible transcription factors HIF-1 alpha and HIF-2 alpha, and the negative regulator of HIF alpha, von Hippel-Lindau protein (VHL), in astrocytes. We found that loss of hypoxic response and VEGF production in astrocytes does not impair normal development of retinal vasculature, indicating that astrocyte-derived VEGF is not essential for this process. In contrast, using a model of oxygen-induced ischemic retinopathy, we show that astrocyte-derived VEGF is essential for hypoxia-induced neovascularization. Thus, we demonstrate that astrocytes in the retina have highly divergent roles during developmental, physiological angiogenesis, and ischemia-driven, pathological neovascularization.
authors.affiliation: Division of Biology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Weidemann
authors.forename: Tim U
authors.initials: TU
authors.lastname: Krohne
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kurihara
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takeda
authors.forename: Michael I
authors.initials: MI
authors.lastname: Dorrell
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007511:Ischemia / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012160:Retina / Q000254:growth & development / Q000502:physiology* / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse; C494469:VHL protein, mouse