We used three preclinical PAD models, including (1) C57BL/6 mice on a high-fat diet (type 2 diabetic model well known to have impaired VEGFR2-eNOS-NO signaling [17,18], (2) eNOS deficient mice (eNOS-KO, that have defective NO generation [19]), and (3) Myoglobin transgenic mice (Mg-Tg, which show defective angiogenesis due to impaired Nitric Oxide (NO) bioavailability [20,21]) in ischemic muscle to determine whether VEGFR1 activation is sufficient to induce angiogenesis and increase perfusion recovery in PAD. The gene discussed is NOS3; the disease is peripheral arterial disease.