Androgen receptor activation inhibits endothelial cell migration in vitro and angiogenesis in vivo

• Published in: European journal of cell biology 2024-12, Vol.103 (4), p.151456, Article 151456
• Main Authors: Huo, Yen-Nien, Yang, Hsiang-Yu, Ke, Hung-Yen, Lin, Chih-Yuan, Tsai, Chien-Sung
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Cell Movement - drug effects; cSrc; CTGF; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Neovascularization, Physiologic - drug effects; Receptors, Androgen - metabolism; RhoA; rhoA GTP-Binding Protein - metabolism; Vascular Endothelial Growth Factor A - metabolism; VEGF; Zebrafish
• ISSN: 0171-9335; 1618-1298; 1618-1298
• DOI: 10.1016/j.ejcb.2024.151456

Our previous research revealed that androgen receptor (AR) activation reduces endothelial cell proliferation via non-genomic pathways. We hypothesized that AR activation might also affect endothelial cell migration, a critical step in angiogenesis. Our data demonstrates that treatment of human umbilical vein endothelial cells (HUVECs) with AR agonists, metribolone (R1881) or dihydrotestosterone (DHT), results in a dose-dependent reduction in migration, which can be reversed by AR antagonists or AR knockdown. Mechanistically, R1881 inhibits HUVEC migration by suppressing RhoA activity through the cSrc/FAK/paxillin pathway and promoting RhoA degradation via RhoA-p27 complex formation, ultimately resulting in RhoA ubiquitination. Transfection with constitutively active RhoA-V14 rescues the inhibitory effect of R1881 on HUVEC migration. Furthermore, R1881 elevates intracellular vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) levels but reduces VEGF secretion from HUVECs. This reduction is attributed to the formation of VEGF-CTGF complexes in the cytosol induced by R1881. Transfection with RhoA-V14 reduces CTGF levels and VEGF-CTGF complex formation, leading to enhanced VEGF secretion. Pre-treatment with WP631, a CTGF inhibitor, mitigates the R1881-induced reduction in VEGF secretion and HUVECs migration. In vivo assessments using zebrafish angiogenesis and mouse matrigel plug assays validate the anti-angiogenic effects of R1881. These findings provide insight into the molecular mechanisms through which AR activation modulates endothelial cell migration and angiogenesis. [Display omitted] •This study is the first to demonstrate that AR activation inhibits endothelial cell migration, revealing a novel regulatory role in vascular biology.•AR agonists like metribolone (R1881) and DHT inhibit endothelial migration dose-dependently, confirming a key pathway for therapeutic exploration.•We uncover that AR regulates migration via RhoA suppression and degradation through cSrc/FAK/paxillin, offering new mechanistic insights.•AR activation’s anti-angiogenic effects are validated in vivo, highlighting its potential as a novel target in vascular disease treatment.•AR significantly reshapes VEGF signaling through VEGF-CTGF complexes, providing fresh insights into hormone-driven angiogenesis regulation.