期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 182, 期 1, 页码 255-265出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2012.09.003
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资金
- March of Dimes
- Harvard Catalyst
- Harvard Clinical and Translational Science Center
- National Heart, Lung, and Blood Institute
- American Heart Association
- American Diabetes Association
- Ellison Foundation
- National Eye Institute Training Grant
- Core Grant for Vision Research
- Research to Prevent Blindness
- NIH [R01EY022084]
- Harvard University
- NATIONAL EYE INSTITUTE [P30EY014104, R01EY023682, R01EY022084] Funding Source: NIH RePORTER
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)
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