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Introduction: Genetic and molecular approaches are increasingly required in the development of effective strategies in treating peripheral vascular diseases (PVD). Glutaredoxin-1 (Grx-1) is involved in redox regulation to protect cells from oxidative stress and to reduce apoptosis. We have shown that Grx-1 overexpression promotes pro-angiogenic and anti-apoptotic mechanisms after MI, leading to improved cardiac repair and reduced ventricular remodeling. This study explored whether Grx-1 overexpression in a mouse model of hind limb ischemia will enhance Ischemia-induced neovascularization and improve recovery. Methods: Hind-limb ischemia was induced in 8-12 week old wild type (WT) mice and Grx-1 transgenic (Grx-1TG) mice through femoral artery ligation. Following ligation, the mice were observed over a 4 weeks period by laser Doppler imaging and the ratio of blood flow in the ischemic to nonischemic limb was documented. Muscle immunohistochemistry was performed to determine the extent of neovascularization, fibrosis and the expression of VEGF, HIF-1α and Ki67.
Results: Grx-1TG mice showed recovery of perfusion when compared to WT on postoperative day14 [0.68±0.04 (n=19) vs. 0.4±0.02 (n=16); p<0.05] and day 21 [0.75±0.03 (n=19) vs. 0.45±0.03 (n=16); p<0.05]. We observed increased capillary [1049±155.4 vs. 501.1±73.6 counts/mm²; p<0.05, n=5], arteriolar density [23.6±1.75 vs. 13.63±0.82 counts/mm²; p<0.05, n=5-6], capillary/myocyte ratio (1.712±0.074 vs. 0.89±0.02; p<0.05, n=5), decreased fibrosis [4.4±0.49 vs. 12.19±0.466 % p<0.05, n=5] and increased VEGF, HIF-1α and Ki67 expression in Grx-1TG vs. WT. Conclusion: Grx-1 overexpression promotes pro-angiogenic factors expression and improves ischemia-induced neovascularization. This increases perfusion in a mouse model of HLI and offers a potential, new therapeutic approach.