Endocrine Abstracts (2017) 49 GP129 | DOI: 10.1530/endoabs.49.GP129

Androgen receptor activation inhibits endothelial cell proliferation through an extra-nuclear signaling pathway

Yen-Nien Huo1, Shauh-Der Yeh2, Chih-Ming Chou3 & Wen-Sen Lee4

1Graduate Institute of Medical Sciences, Medical College, Taipei Medical University, Taipei 110, Taiwan; 2Departments of Urology, Taipei 110, Taiwan; 3Departments of Biochemistry and Molecular Cell Biology, Taipei 110, Taiwan; 4Departments of Physiology, School of Medicine, Medical College, Taipei Medical University, Taipei 110, Taiwan.

The effect of androgen on angiogenesis has been documented. However, its molecular mechanisms underlying has not been well illustrated. Here, we show that treatment with an androgen receptor (AR) agonist, metribolone (R1881) at a range of concentrations (0.05–5 nM) or dihydrotestosterone (DHT) at a range of concentrations (0.4–40 nM) caused concentration-dependent inhibition of proliferation in human umbilical venous endothelial cells (HUVEC). The R1881-induced proliferation inhibition was also observed in human dermal microvascular endothelial cells (HDMVE). Blockade of the AR activity by pre-treatment with HF (5 nM), an AR antagonist, or knockdown of AR expression using the shRNA technique abolished the R1881-induced proliferation inhibition in HUVEC, suggesting that AR receptor activation can inhibit endothelial cell proliferation. To further delineate the signaling pathway involved in the AR activation-induced proliferation inhibition, our data indicate that R1881 inhibited proliferation in vascular endothelial cells through activating the AR/cSrc/AKT/p38/ERK/NFκB signaling pathway, which in turn up-regulated the expression of p53, p21 and p27 protein, and finally reduced endothelial cell proliferation. Using the zebrafish model, we also demonstrate that R1881 inhibited angiogenesis through the AR-mediated pathway in vivo. The findings of the present study highlight the molecular mechanisms underlying AR activation-induced proliferation inhibition in vascular endothelial cells.

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