Estrogen-related receptor α is involved in angiogenesis and skeletal muscle revascularization in hindlimb ischemia.

Danesh H Sopariwala, Neah Likhite, Gungsheng Pei, Fnu Haroon, Lisa Lin, Vikas Yadav, Zhongming Zhao, Vihang A Narkar

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2021 May

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Skeletal muscle ischemia is a major consequence of peripheral arterial disease (PAD) or critical limb ischemia (CLI). Although therapeutic options for resolving muscle ischemia in PAD/CLI are limited, the issue is compounded by poor understanding of the mechanisms driving muscle vascularization. We found that nuclear receptor estrogen-related receptor alpha (ERRα) expression is induced in murine skeletal muscle by hindlimb ischemia (HLI), and in cultured myotubes by hypoxia, suggesting a potential role for ERRα in ischemic response. To test this, we generated skeletal muscle-specific ERRα transgenic (TG) mice. In these mice, ERRα drives myofiber type switch from glycolytic type IIB to oxidative type IIA/IIX myofibers, which are typically associated with more vascular supply in muscle. Indeed, RNA sequencing and functional enrichment analysis of TG muscle revealed that "paracrine angiogenesis" is the top-ranked transcriptional program activated by ERRα in the skeletal muscle. Immunohistochemistry and angiography showed that ERRα overexpression increases baseline capillarity, arterioles and non-leaky blood vessel formation in the skeletal muscles. Moreover, ERRα overexpression facilitates ischemic neo-angiogenesis and perfusion recovery in hindlimb musculature of mice subjected to HLI. Therefore, ERRα is a hypoxia inducible nuclear receptor that is involved in skeletal muscle angiogenesis and could be potentially targeted for treating PAD/CLI. © 2021 Federation of American Societies for Experimental Biology.

Citation

Danesh H Sopariwala, Neah Likhite, Gungsheng Pei, Fnu Haroon, Lisa Lin, Vikas Yadav, Zhongming Zhao, Vihang A Narkar. Estrogen-related receptor α is involved in angiogenesis and skeletal muscle revascularization in hindlimb ischemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2021 May;35(5):e21480