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A. Scott, M. Fruttiger; Astrocyte-Derived Vascular Endothelial Growth Factor in Vessel Survival and Regeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2056.
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Vascular endothelial growth factor (VEGF) plays a complex role in angiogenesis. Whilst being essential during embryonic development, it also causes pathological angiogenesis in ischemic retinopathies including diabetic retinopathy. A key stimulus for VEGF expression is hypoxia which, under pathological conditions, is typically caused by loss of capillaries. This can trigger regenerative revascularization in model systems, but harnessing this process to cure ischemic retinopathies has so far been an elusive target. In light of the increasing use of anti-VEGF therapies for treatment of aberrant angiogenesis, we investigated the role of VEGF in vessel survival and regeneration.
In order to study hypoxia sensing and VEGF expression in retinal astrocytes, we crossed transgenic mice expressing Cre recombinase in retinal astrocytes (Gfap-Cre mice) with Vegf-floxed mice as well as with Vhl-floxed mice. This results in deletion of VEGF or VHL specifically in retinal astrocytes. Pups were sacrificed at postnatal day 5 (P5) to examine normal vascular development. Furthermore, the oxygen-induced retinopathy (OIR) model was used to investigate sensitivity to vaso-obliteration and vascular regeneration. To this end, pups were exposed to hyperoxia between P7-P12 and capillary-obliteration was assessed at P12. Other pups were returned to room air and revascularization was studied at P17.
In Gfap-Cre/Vegf/f mutant mice the retinal vasculature developed normally. In contrast, capillary obliteration in the OIR model was markedly augmented (compared to Cre negative littermates), and regenerative sprouting was reduced (at P17) in these mice. In Gfap-Cre/Vhlf/f mice we found some clustering of central capillaries at P5 but vaso-obliteration occurred at normal rates in un-clustered vessels.
Astrocyte-derived VEGF is not required for vascular development but protects capillaries from hyperoxia induced vaso-obliteration. This is unlikely to be mediated via the HIF pathway as VHL deletion in astrocytes did not protect from vaso-obliteration. Furthermore, VEGF is important for healthy revascularization, indicating that anti-VEGF therapies should be administered with caution.
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