Androgen Receptor Promotes Gender-Independent Angiogenesis in Response to Ischemia and is Required for Activation of VEGF Receptor Signaling
Background—Hypoandrogenemia is associated with an increased risk of ischemic diseases. Since actions of androgens are exerted through androgen receptor (AR) activation, we studied hind limb ischemia in AR knockout (KO) mice to elucidate the role of AR in response to ischemia.
Methods and Results—Both male and female ARKO 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 ARKO mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase (eNOS) 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 eNOS. Immunoprecipitation experiments documented an association between AR and kinase insert domain protein receptor (KDR) that promoted the recruitment of downstream signaling components.
Conclusions—These results document a physiological role of AR in gender-independent angiogenic potency and provide evidence for a novel cross-talk between androgen/AR signaling and VEGF/KDR signaling pathways.
- Received January 25, 2013.
- Revision received May 2, 2013.
- Accepted May 16, 2013.