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Published on: June 30, 2023
Androgen receptor activation inhibits endothelial cell migration in vitro and angiogenesis in vivo
Yen-Nien Huo1, Hsiang-Yu Yang1, Hung-Yen Ke1
1Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
Abstract:
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.
Insights
Androgen receptor (AR) activation inhibits endothelial cell migration and angiogenesis by affecting RhoA activity and VEGF secretion. This research clarifies AR
Area of Science:
- Endocrinology and Cell Biology
- Molecular Mechanisms of Angiogenesis
Background:
- Androgen receptor (AR) activation was previously shown to reduce endothelial cell proliferation through non-genomic pathways.
- Endothelial cell migration is a crucial process in angiogenesis, making it a potential target for AR modulation.
Purpose of the Study:
- To investigate the effect of AR activation on endothelial cell migration.
- To elucidate the molecular mechanisms underlying AR-mediated regulation of endothelial cell migration and angiogenesis.
Main Methods:
- Treatment of human umbilical vein endothelial cells (HUVECs) with AR agonists (metribolone, dihydrotestosterone) and antagonists.
- AR knockdown, RhoA activity assays, and RhoA degradation studies (ubiquitination, p27 complex formation).
- Intracellular and secreted VEGF and CTGF level analysis, in vivo zebrafish and mouse matrigel plug assays.
Main Results:
- AR activation dose-dependently reduced HUVEC migration, an effect reversed by AR antagonists or knockdown.
- AR agonists suppressed RhoA activity via the cSrc/FAK/paxillin pathway and promoted RhoA degradation, leading to reduced HUVEC migration.
- AR activation increased intracellular VEGF and CTGF but decreased VEGF secretion due to VEGF-CTGF complex formation, inhibiting angiogenesis in vivo.
Conclusions:
- AR activation inhibits endothelial cell migration and angiogenesis through mechanisms involving RhoA regulation and altered VEGF/CTGF dynamics.
- The findings reveal novel molecular pathways by which AR signaling impacts vascular development.
- Targeting AR signaling may offer therapeutic strategies for angiogenesis-related diseases.
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