Abstract
Mechanisms for the lack of efficacy of anti-angiogenic strategies for cancer have not been elucidated. We previously demonstrated that up-regulated glutaredoxin-1 (Glrx) inhibited endothelial cell (EC) angiogenic properties. Glrx is a small cytosolic enzyme which reverses glutathione adducts on protein thiols. Global Glrx transgenic mice had impaired ischemic limb vascularization, while Glrx knockout mice showed enhanced ischemic revascularization in association with HIF-1a activation. Here we generated EC-specific Glrx transgenic mice (EC-Glrx TG) by crossing VE-cadherin tTA mice and tet-operated Glrx mice. Similar to global Glrx TG mice, EC-Glrx TG mice showed impaired blood flow recovery after femoral artery ligation. Subcutaneous Matrigel implants contained significantly lower hemoglobin content compared to control mice, indicating less EC migration in EC-Glrx TG mice. Potential suppression of tumor angiogenesis was tested in EC-Glrx TG mice. When B16F0 mouse melanoma cells were subcutaneously implanted for 2 weeks, isolectin B4 staining in tumors indicated fewer EC markers in EC-Glrx TG tumors. Unexpectedly, B16F0 tumor weight was not inhibited, but rather dramatically promoted in EC-Glrx TG mice (667 ± 160 vs. 1229 ± 202 mg, n=12, 8, respectively, P
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