title: PGC1β activates an antiangiogenic program to repress neoangiogenesis in muscle ischemia.
abstract: Revascularization of ischemic skeletal muscle is governed by a balance between pro- and antiangiogenic factors in multiple cell types but particularly in myocytes and endothelial cells. Whereas the regulators of proangiogenic factors are well defined (e.g., hypoxia-inducible factor [HIF]), the transcriptional pathways encoding antiangiogenic factors remain unknown. We report that the transcriptional cofactor PGC1β drives an antiangiogenic gene program in muscle and endothelial cells. PGC1β transcriptionally represses proangiogenic genes (e.g., Vegfc, Vegfd, Pdgfb, Angpt1, Angpt2, Fgf1, and Fgf2) and induces antiangiogenic genes (e.g., Thbs1, Thbs2, Angstat, Pedf, and Vash1). Consequently, muscle-specific PGC1β overexpression impairs muscle revascularization in ischemia and PGC1β deletion enhances it. PGC1β overexpression or deletion in endothelial cells also blocks or stimulates angiogenesis, respectively. PGC1β stimulates the antiangiogenic genes partly by coactivating COUP-TFI. Furthermore, proangiogenic stimuli such as hypoxia, hypoxia-mimetic agents, and ischemia decrease PGC1β expression in a HIF-dependent manner. PGC1β is an antiangiogenic transcriptional switch that could be targeted for therapeutic angiogenesis.
authors: Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, 1825 Pressler Street, Houston, TX 77030, USA.
authors: Vikas
authors: V
authors: Yadav
authors: Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, 1825 Pressler Street, Houston, TX 77030, USA.
authors: Antonios
authors: A
authors: Matsakas
authors: Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, 1825 Pressler Street, Houston, TX 77030, USA.
authors: Sabina
authors: S
authors: Lorca
authors: Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, 1825 Pressler Street, Houston, TX 77030, USA; Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, University of Texas Medical School at Houston, 6767 Bertner Avenue, Houston, TX 77030, USA. Electronic address: vihang.a.narkar@uth.tmc.edu.
authors: Vihang A
authors: VA
authors: Narkar
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D018919:Neovascularization, Physiologic; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D042501:Angiogenic Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors