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-1α and HIF-2α, and the negative regulator of HIFα, 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.

Connective Tissue Growth Factor Regulates Retinal Neovascularization through p53 Protein-dependent Transactivation of the Matrix Metalloproteinase (MMP)-2 Gene

“…These data are consistent with those reported by others, although small discrepancies in the extent of mRNA level changes exist due to the well known variability of the retinopathy response in mice (40,41). Nevertheless, ischemia-induced retinal neovascularization requires neither TNF-␣ nor IL-1␤, which have been shown to affect mostly leukostasis and vascular leakage in the OIR mouse model (42).…”

Hypoxia-Inducible Transcription Factors Stabilization in the Thick Ascending Limb Protects against Ischemic Acute Kidney Injury

“…To determine relative gene deletion by Cre-mediated excision in TALs, copies of the floxed allele quantified by real-time PCR were compared with a WT allele as described previously. 67 …”

Roles of Hypoxia Response in Retinal Development and Pathophysiology

“…21,22 Amacrine and horizontal cell-specific Hif-1α knockout mice also showed a decreased density of vascular plexus in the intermediate retinal layer where these cells are located. 23 In contrast, we found that deletion of Vegf, Hif-1α, or Hif-2α specifically in astrocyte glia (which forms as a template for the retinal vasculature) did not induce phenotypic change during retinal vascular development 24 although another group reported a dissimilar phenotype of glia-specific Hif-2a knockout mice utilizing a different Cre transgenic mouse line. 25 Our findings indicated that the hypoxia response in neurons, rather than in glia, is important during physiological retinal vascular development and acts to control Vegf expression.…”