Integrative Physiology Revascularization of Ischemic Skeletal Muscle by Estrogen-Related Receptor-

Rationale: Oxidative myofibers in the skeletal muscles express high levels of angiogenic factors, have dense vasculature, and promptly revascularize during ischemia. Estrogen-related receptor-gamma (ERR ) activates genes that govern metabolic and vascular features typical to oxidative myofibers. Therefore, ERR -dependent remodeling of the myofibers may promote neoangiogenesis and restoration of blood perfusion in skeletal muscle ischemia. Objective: To investigate the muscle fiber type remodeling by ERR and its role in the vascular recovery of ischemic muscle. Methods and Results: Using immunohistology, we show that skeletal muscle-specific transgenic overexpression of ERR increases the proportions of oxidative and densely vascularized type IIA and IIX myofibers and decreases glycolytic and less vascularized type IIB myofibers. This myofiber remodeling results in a higher basal blood flow in the transgenic skeletal muscle. By applying unilateral hind limb ischemia to transgenic and wild-type mice, we found accelerated revascularization (fluorescent microangiography), restoration of blood perfusion (laser Doppler flowmetry), and muscle repair (Evans blue dye exclusion) in transgenic compared to wild-type ischemic muscles. This ameliorative effect is linked to enhanced neoangiogenesis (CD31 staining and microfil perfusion) by ERR . Using cultured muscle cells in which ERR is inactivated, we show that the receptor is dispensable for the classical hypoxic response of transcriptional upregulation and secretion of vascular endothelial growth factor A. Rather, the ameliorative effect of ERR is linked to the receptor-mediated increase in oxidative myofibers that inherently express and secrete high levels of angiogenic factors. Conclusions: The ERR is a hypoxia-independent inducer of neoangiogenesis that can promote reparative revascularization. (Circ Res. 2012;110:1087-1096.)