Abstract 12873: Androgen Receptor is Essential for Cell Survival and Neovascularization After Ischemia.
Background: Androgens, male sex hormones, exert their biological effects in various target organs by genomic and non-genomic actions through the androgen receptor (AR) activation. Recently, we have demonstrated that the androgen-AR system plays protective roles against angiotensin II-induced cardiovascular remodeling. However, it is unclear whether the androgen-AR system is involved in response to ischemic stress.
Methods & Results: In order to create a hindlimb ischemia model, unilateral femoral artery ligation was performed in male AR knockout (KO) mice and littermate wild-type (WT) mice at 25 weeks of age. Ischemia-induced hindlimb autoamputation was found in 53% of ARKO but not in WT after ischemia. In addition, blood flow recovery was markedly impaired with decreased capillary density in ARKO compared to that in WT. TUNEL-positive nuclei in ischemic muscles were 2.7 times increased in ARKO compared to those in WT. Bcl2-to-Bax expression ratio in ischemic muscle was significantly lower in ARKO than in WT. In aortic ring assay and in vivo angiogenesis assay, AR deficiency decreased angiogenic potency of endothelial cells. Neither autoamputation nor impaired blood flow recovery were rescued by WT bone marrow cell transplantation in ARKO after hindlimb ischemia. Gene expression levels of angiogenic factors, including VEGF, were prominently increased in ischemic muscle of ARKO compared to those in WT. However, gene expression level of Kdr as a critical VEGF receptor was apparently reduced in ARKO compared to that in WT. In addition, mRNA of Bai 1 as an angiogenesis inhibitory factor was maintained at a higher expression level in ARKO than in WT after ischemia. In ischemic muscle of ARKO, reduced phosphorylations of ERK1/2, Akt and eNOS were observed compared to those in WT. In in vitro studies, AR SiRNA attenuated VEGF-stimulated phosphorylations of Akt and eNOS in HUVECs suggesting that AR deficiency causes impaired downstream signal transduction of Kdr.
Conclusions: In male ARKO, ischemia causes acceleration of cellular apoptosis and impaired angiogenesis with dysregulation of the expression levels of angiogenic and anti-angiogenic factors. Therefore, androgen receptor is essential for cell survival and neovascularization after ischemia in males.
- © 2010 by American Heart Association, Inc.