Androgen receptor promotes angiogenesis in response to ischemia via activation of VEGF receptor signaling pathway regardless of sex

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 355-388-Sex Hormone Receptor Action & Reaction
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-364
Sumiko Yoshida*, Ken-Ichi Aihara, Yasumasa Ikeda and Toshio Matsumoto
The University of Tokushima Graduate School, Tokushima, Japan
Introduction & Objective:  Hypoandrogenemia with aging called “andropause” is associated with an increased risk of ischemic cardiovascular diseases. On the other hands, the role of androgens in cardiovascular physiology and pathophysiology remains controversial.   Androgens exert various actions in its target organs through androgen receptor (AR) activation.  Recently, we have demonstrated that AR activation plays a pivotal role in protection from pathological cardiovascular remodeling induced by angiotensin II and cardiotoxicity induced by doxorubicin.  However, it has been unclear whether AR plays a pathophysiological role in ischemia of cardiovascular system.  In order to clarify this issue, we studied a hind limb ischemia model in male and female AR knockout (KO) mice to elucidate the role of AR in response to ischemic injury.

Methods & Results:  Surgical arteriectomy of the unilateral femoral artery was performed in both male and female ARKO mice and littermate wild-type (WT) mice at 25 weeks of age.  Ischemia-induced hindlimb autoamputation was observed 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.  In ex vivo and in vivo angiogenesis assays, AR-deficient vascular endothelial cells showed reduced angiogenic potency.   Ischemia-induced higher cellular apoptosis and lower Bcl2-to-Bax expression ratio in ischemic skeletal muscles were observed in both gender of ARKO mice compared to those in WT mice.  In bone marrow transplantation between male WT and male ARKO mice, WT bone marrow cells are not involved in impaired angiogenic response in ARKO mice after hindlimb ischemia.  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.  In in vitro studies, siRNA-mediated knockdown of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and eNOS.  Furthermore, immunoprecipitation experiments showed that AR is associated with kinase insert domain protein receptor (KDR), Src and PI3K, leading to activation of Akt and eNOS.

Conclusions:  These results demonstrate that AR activation promotes angiogenesis in response to ischemia regardless of sex.  In addition, they provide evidence for a novel cross-talk between AR signaling and VEGF/KDR signaling pathways.

Nothing to Disclose: SY, KIA, YI, TM

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