PGC1β Activates an Antiangiogenic Program to Repress Neoangiogenesis in Muscle Ischemia

• Main Authors: Vikas Yadav, Antonios Matsakas, Sabina Lorca, Vihang A. Narkar
• Format: Article
• Language: English
• Published: Elsevier 2014-08-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124714005245

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.