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Aihua Jiang, Stephanie Abend, Patricia A. D'Amore, Magali Saint-Geniez, Zolt Arany; The Transcriptional Coactivator PGC-1alpha Regulates Normal and Pathological Angiogenesis in the Retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3975.
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PGC-1alpha is a transcriptional coactivator that plays a central role in regulation of cellular energy metabolism. In skeletal tissue, PGC-1alpha induces VEGF expression and promotes angiogenesis independently from the canonical HIF1alpha pathway. The goal of this study was to determine the role of PGC-1alpha during normal retinal vascularization and in the model of oxygen-induced retinopathy (OIR).
PGC-1alpha expression was analyzed by quantitative PCR (qPCR) on retinal mRNA isolated during normal postnatal development and OIR model. OIR model was induced by exposing WT and PGC-1alpha -/- mouse pups to 75% oxygen between postnatal (P) days 7 and 12. Vascular outgrowth, capillaries density and arterio-venous patterning was quantified on P4, P13 and adult PGC-1alpha-/- retinas stained with isolectin-B4, collagen IV or smooth muscle actin. Effects of hypoxia and PGC-1alpha overexpression in RPE, photoreceptor, ganglion, and Muller cell lines (ARPE-19, 661W, RGC5, and MIOM1 respectively) were determined by qPCR analysis.
Overexpression of PGC-1alpha caused 2 - 5 folds induction of VEGF expression in photoreceptors, ganglion and Müller cells, but not in RPE. In intact retinas, PGC-1alpha expression is strongly upregulated during postnatal development with a maximal induction at P15. PGC-1alpha -/- mice had a significant reduction of retinal vascular outgrowth at P4. Abnormal vascular development was associated with reduced capillary density and number of main arteries and veins. In the OIR model, PGC-1alpha -/- mice were protected against pathological neovascularization as shown by a significant reduction of neovascular and avascular area.
These data demonstrate that PGC-1alpha regulates VEGF in a number of retinal cell types, is strongly expressed in the retina, and is required for normal vessel development and for pathologic neovascularization in the OIR model. PGC-1alpha thus likely co-regulates metabolic programs with angiogenesis in the retina, thereby coordinating oxygen consumption with delivery. The results also highlight PGC-1alpha as a novel target in the treatment of ROP.
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