Abstract 12957: Androgen Receptor is Required for Cellular Survival and Angiogenesis in Response to Ischemia via Activation of VEGF Receptor Signaling Pathway Regardless of Sex
Introduction and Objective: Androgens exert various biological actions in their target organs through androgen receptor (AR) activation. Recently, we have demonstrated that AR activation plays a pivotal role in protection from angiotensin II-induced cardiovascular remodeling and doxorubicin-induced cardiotoxicity. However, it has been unclear whether AR plays a pathophysiological role in response to ischemic stimuli. In order to clarify this issue, we studied the role of AR in response to ischemic injury using a hindlimb ischemia model in both male and female AR knockout (KO) mice.
Methods and Results: Unilateral femoral artery ligation was performed in both sexes of ARKO mice and littermate wild-type (WT) mice at 25 weeks of age. Ischemia-induced hindlimb autoamputation was found in about half of the ARKO mice but not in WT mice at 21 days after ischemia regardless of sex. In addition, blood flow recovery was markedly impaired with decreased capillary density in both sexes of ARKO mice compared to those in WT mice. Sex-independent higher TUNEL-positive nuclei and lower Bcl2-to-Bax expression ratio in ischemic skeletal muscles were observed in ARKO mice compared to those in WT mice. In ischemic limbs of both sexes of ARKO mice, impaired phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) was observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor (VEGF) gene expression. WT bone marrow cell transplantation did not rescue the impaired angiogenic response in ARKO mice after hindlimb ischemia. Aortic ring assay and matrigel implantation studies revealed reduction in angiogenic potency of AR-deficient vascular endothelial cells. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and eNOS. Furthermore, immunoprecipitation experiments showed that AR is required for complex formation with kinase insert domain protein receptor (KDR), Src and PI3K, leading to activation of Akt and eNOS.
Conclusions: AR activation promotes gender-independent cell survival and angiogenesis in response to ischemia through a novel cross-talk between AR and VEGF/KDR signaling pathways.
- © 2012 by American Heart Association, Inc.