PGC1β activates an antiangiogenic program to repress neoangiogenesis in muscle ischemia

Yadav, Vikas; Matsakas, Antonios; Lorca, Sabina; Narkar, Vihang A.

Abstract

Revascularization of ischemic skeletalmuscle 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, musclespecific 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, roangiogenic 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.

Citation

Yadav, V., Matsakas, A., Lorca, S., & Narkar, V. A. (2014). PGC1β activates an antiangiogenic program to repress neoangiogenesis in muscle ischemia. Cell reports, 8(3), 783-797. https://doi.org/10.1016/j.celrep.2014.06.040

• Acceptance Date: Jun 20, 2014
• Online Publication Date: Jul 24, 2014
• Publication Date: Aug 7, 2014
• Deposit Date: May 20, 2015
• Publicly Available Date: May 20, 2015
• Journal: Cell reports
• Print ISSN: 2211-1247
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 3
• Pages: 783-797
• DOI: https://doi.org/10.1016/j.celrep.2014.06.040
• Keywords: Neoangiogenesis, Muscle ischemia, PGC1β
• Public URL: https://hull-repository.worktribe.com/output/374077
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S2211124714005245
• Additional Information: Copy of article first published in: Cell reports, 2014, v.8, issue 3.
• Contract Date: May 20, 2015