Androgen receptor promotes sex-independent angiogenesis in response to ischemia and is required for activation of vascular endothelial growth factor receptor …

S Yoshida, K Aihara, Y Ikeda, Y Sumitomo-Ueda… - Circulation, 2013 - Am Heart Assoc
S Yoshida, K Aihara, Y Ikeda, Y Sumitomo-Ueda, R Uemoto, K Ishikawa, T Ise, S Yagi…
Circulation, 2013Am Heart Assoc
Background—Hypoandrogenemia is associated with an increased risk of ischemic
diseases. Because actions of androgens are exerted through androgen receptor (AR)
activation, we studied hind-limb ischemia in AR knockout mice to elucidate the role of AR in
response to ischemia. Methods and Results—Both male and female AR knockout mice
exhibited impaired blood flow recovery, more cellular apoptosis, and a higher incidence of
autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient …
Background
Hypoandrogenemia is associated with an increased risk of ischemic diseases. Because actions of androgens are exerted through androgen receptor (AR) activation, we studied hind-limb ischemia in AR knockout mice to elucidate the role of AR in response to ischemia.
Methods and Results
Both male and female AR knockout mice exhibited impaired blood flow recovery, more cellular apoptosis, and a higher incidence of autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient vascular endothelial cells showed reduced angiogenic capability. In ischemic limbs of AR knockout mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase were observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor (VEGF) gene expression. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and endothelial nitric oxide synthase. Immunoprecipitation experiments documented an association between AR and kinase insert domain protein receptor that promoted the recruitment of downstream signaling components.
Conclusions
These results document a physiological role of AR in sex-independent angiogenic potency and provide evidence of novel cross-talk between the androgen/AR signaling and VEGF/kinase insert domain protein receptor signaling pathways.
Am Heart Assoc