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To test this hypothesis, we created femoral artery ligation in wild-type and heterozygous cystathionine \u03b2-synthase (CBS<jats:sup>+\/\u2212<\/jats:sup>) mice (a model for HHcy) and assessed tissue perfusion, collateral vessel formation, and skeletal muscle function using laser-Doppler perfusion imaging, barium angiography, and fatigue tests. In addition, we assessed postischemic levels of VEGF and levels of its muscle-specific regulators: hypoxia-inducible factor (HIF)-1\u03b1 and peroxisome proliferator-activated receptor-\u03b3 coactivator (PGC)-1\u03b1. The observations indicated dysregulation of VEGF, HIF-1\u03b1, and PGC-1\u03b1 levels in ischemic skeletal muscles of CBS<jats:sup>+\/\u2212<\/jats:sup> mice. Concomitant with the reduced ischemic angiogenic responses, we also observed diminished leptin expression and attenuated Akt signaling in ischemic muscle fibers of CBS<jats:sup>+\/\u2212<\/jats:sup> mice. Moreover, there was enhanced atrogene, ubiquitin ligases that conjugate proteins for degradation during muscle atrophy, transcription, and reduced muscle function after ischemia in CBS<jats:sup>+\/\u2212<\/jats:sup> mice. These results suggest that HHcy adversely affects muscle-specific ischemic responses and contributes to muscle frailty. <\/jats:p>","DOI":"10.1152\/ajpheart.00003.2014","type":"journal-article","created":{"date-parts":[[2014,3,1]],"date-time":"2014-03-01T06:50:28Z","timestamp":1393656628000},"page":"H1116-H1127","source":"Crossref","is-referenced-by-count":23,"title":["Hyperhomocysteinemia attenuates angiogenesis through reduction of HIF-1\u03b1 and PGC-1\u03b1 levels in muscle fibers during hindlimb ischemia"],"prefix":"10.1152","volume":"306","author":[{"given":"Sudhakar","family":"Veeranki","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srikanth","family":"Givvimani","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Louisville, Louisville, 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