title: PGC-1α regulates normal and pathological angiogenesis in the retina.
abstract: 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-1α is a transcriptional coactivator that plays a central role in the regulation of cellular metabolism. In skeletal muscle, PGC-1α induces VEGFA expression and powerfully promotes angiogenesis, suggesting a similar role in other tissues. This study investigates the role of PGC-1α during normal and pathological vascularization in the retina. We show that PGC-1α induces the expression of VEGFA in numerous retinal cells, and that PGC-1α expression is strongly induced during postnatal retinal development, coincident with VEGFA expression and angiogenesis. PGC-1α(-/-) 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-1α expression is dramatically induced in the inner nuclear layer of the retina, suggesting that PGC-1α drives pathological neovascularization. In support of this, PGC-1α(-/-) mice subjected to oxygen-induced retinopathy had decreased expression of VEGFA and were protected against pathological neovascularization. These results demonstrate that PGC-1α regulates VEGFA in the retina and is required for normal vessel development and for pathological neovascularization. The data highlight PGC-1α as a novel target in the treatment of neovascular diseases of the eye.
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, USA.
authors.forename: Magali
authors.initials: M
authors.lastname: Saint-Geniez
authors.forename: Aihua
authors.initials: A
authors.lastname: Jiang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Abend
authors.forename: Laura
authors.initials: L
authors.lastname: Liu
authors.forename: Harry
authors.initials: H
authors.lastname: Sweigard
authors.forename: Kip M
authors.initials: KM
authors.lastname: Connor
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Arany
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012160:Retina / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D012171:Retinal Vessels / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000378:metabolism / Q000517:prevention & control; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse