Research Article E-Selectin/AAV Gene Therapy Promotes Myogenesis and Skeletal Muscle Recovery in a Mouse Hindlimb Ischemia Model Antoine J. Ribieras , 1 Yulexi Y. Ortiz, 1 Yan Li, 1 Nga T. Le, 1 Carlos T. Huerta , 1 Francesca A. Voza, 1 Hongwei Shao , 1 Roberto I. Vazquez-Padron , 1,2 Zhao-Jun Liu , 1,2 and Omaida C. Velazquez 1,2 1 Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA 2 Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA Correspondence should be addressed to Zhao-Jun Liu; zliu@med.miami.edu and Omaida C. Velazquez; ovelazquez@med.miami.edu Received 15 February 2023; Revised 25 April 2023; Accepted 10 May 2023; Published 19 May 2023 Academic Editor: Baohui Xu Copyright © 2023 Antoine J. Ribieras et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The response to ischemia in peripheral artery disease (PAD) depends on compensatory neovascularization and coordination of tissue regeneration. Identifying novel mechanisms regulating these processes is critical to the development of nonsurgical treatments for PAD. E-selectin is an adhesion molecule that mediates cell recruitment during neovascularization. Therapeutic priming of ischemic limb tissues with intramuscular E-selectin gene therapy promotes angiogenesis and reduces tissue loss in a murine hindlimb gangrene model. In this study, we evaluated the effects of E-selectin gene therapy on skeletal muscle recovery, specifically focusing on exercise performance and myofiber regeneration. C57BL/6J mice were treated with intramuscular E- selectin/adeno-associated virus serotype 2/2 gene therapy (E-sel/AAV) or LacZ/AAV2/2 (LacZ/AAV) as control and then subjected to femoral artery coagulation. Recovery of hindlimb perfusion was assessed by laser Doppler perfusion imaging and muscle function by treadmill exhaustion and grip strength testing. After three postoperative weeks, hindlimb muscle was harvested for immunofluorescence analysis. At all postoperative time points, mice treated with E-sel/AAV had improved hindlimb perfusion and exercise capacity. E-sel/AAV gene therapy also increased the coexpression of MyoD and Ki-67 in skeletal muscle progenitors and the proportion of Myh7 + myofibers. Altogether, our findings demonstrate that in addition to improving reperfusion, intramuscular E-sel/AAV gene therapy enhances the regeneration of ischemic skeletal muscle with a corresponding benefit on exercise performance. These results suggest a potential role for E-sel/AAV gene therapy as a nonsurgical adjunct in patients with life-limiting PAD. 1. Introduction Peripheral artery disease (PAD) is the manifestation of sys- temic atherosclerosis in the extremities. PAD affects 8.5 mil- lion people in the United States and more than 200 million worldwide [1]. Symptomatic patients with PAD typically present with exertional calf pain known as intermittent clau- dication [1–3]. The pathophysiology of intermittent claudi- cation in PAD is related to both impaired perfusion and skeletal muscle dysfunction [4, 5]. Histologically, decreased size and abnormal morphology of myofibers correlate with functional impairments such as calf muscle strength and walking distance [6]. Neovascularization depends on the recruitment of endothelial progenitor cells (EPCs), remodel- ing of the tissue microenvironment, and coordination of endothelial sprouting [7]. On the other hand, skeletal muscle regeneration requires the activation, proliferation, and dif- ferentiation of muscle stem cells known as satellite cells. Nevertheless, there is considerable overlap between these two processes during the regeneration of ischemic muscle. Several growth factors have been shown to play a role in the regulation of both neovascularization and skeletal Hindawi Cardiovascular erapeutics Volume 2023, Article ID 6679390, 10 pages https://doi.org/10.1155/2023/6679390