PGC-1 alpha Regulates Normal and Pathological Angiogenesis in the Retina

Neovascular diseases of the eye are the most common causes of blindness worldwide. The mechanisms underlying pathological neovascularization in the retina remain incompletely understood. PGC-1 alpha is a transcriptional coactivator that plays a central role in the regulation of cellular metabolism. In skeletal muscle, PGC-1 alpha induces VEGFA expression and powerfully promotes angiogenesis, suggesting a similar rote in other tissues. This study investigates the role of PGC-1 alpha during normal and pathological vascularization in the retina. We show that PGC-1 alpha induces the expression of VEGFA in numerous retinal cells, and that PGC-1 alpha expression is strongly induced during postnatal retinal development, coincident with VEGFA expression and angiogenesis. PGC-1 alpha(-/-) mice have a significant reduction of early retinal vascular outgrowth, and reduced density of capillaries and number of main arteries and veins as adults. In the oxygen-induced retinopathy model of retinopathy of prematurity, PGC-1 alpha expression is dramatically induced in the inner nuclear layer of the retina, suggesting that PGC-1 alpha drives pathological neovascularization. In support of this, PGC-1 alpha(-/-) mice subjected to oxygen-induced retinopathy had decreased expression of VEGFA and were protected against pathological neovascularization. These results demonstrate that PGC-1 alpha regulates VEGFA in the retina and is required for normal vessel development and for pathological neovascularization. The data highlight PGC-1 alpha as a novel target in the treatment of neovascular diseases of the eye. (Am 3 Pathol 2013, 182: 255-265; http://dx.doiorg/10.1016/j.ajpath.2012.09.003)