ENDOTHELIAL REGULATION OF eNOS, PAI-1 AND t-PA BY TESTOSTERONE AND DIHYDROTESTOSTERONE IN VITRO AND IN VIVO

L. GOGLIA; V. TOSI; A.M. SANCHEZ; M.I. FLAMINI; X-D. FU; S. ZULLINO; A.R. GENAZZANI; T. SIMONCINI

MOLECULAR HUMAN REPRODUCTION.

OXFORD UNIV PRESS

Año: 2010

1360-9947

The aim of this study is the identification of direct endothelial regulation by the androgens testosterone (T) and dihydrotestosterone (DHT).We tested the effects of T and DHT on nitric oxide (NO) synthesis and on tissue plasminogen activator (t- PA) and plasminogen activator inhibitor-1 (PAI-1) expression in human endothelial cells and in ovariectomized rats.The results showed that at physiological concentrations T and DHT increase endothelial synthesis of NO. This depends on a rapid recruitment of the extracellular-related kinase (ERK)1/2 and of the phosphatidylinositol 3-OH kinase (PI3K)/Akt cascades, resulting in endothelial nitric oxide synthase (eNOS) Ser1177-phosphorylation. In addition, a later increase of eNOS expression is found. With supraphysiological amounts of T or DHT the induction of NO synthesis is lost. A concentration-related increase of t-PA expression starting from physiological concentrations of T or DHT is found, while PAI-1 is augmented only with higher doses. While DHT exerts these actions through androgen receptors (AR), T acts in part through aromatase-dependent conversion to 17â-estradiol. Ovariectomy is associated with significant changes in eNOS, t-PA and PAI-1 expression in the aorta of Wistar rats and T and DHT result in modifications on eNOS, PAI-1 and t-PA that are in line with the in vitro experiments. In conclusion, T and DHT act on endothelial cells through AR or via conversion to estradiol. Physiological, but not higher amounts are associated with enhanced NO synthesis and an increased t- PA/PAI-1 ratio. These findings are useful to understand the impact of androgens in ageing individuals.In conclusion, T and DHT act on endothelial cells through AR or via conversion to estradiol. Physiological, but not higher amounts are associated with enhanced NO synthesis and an increased t- PA/PAI-1 ratio. These findings are useful to understand the impact of androgens in ageing individuals.The results showed that at physiological concentrations T and DHT increase endothelial synthesis of NO. This depends on a rapid recruitment of the extracellular-related kinase (ERK)1/2 and of the phosphatidylinositol 3-OH kinase (PI3K)/Akt cascades, resulting in endothelial nitric oxide synthase (eNOS) Ser1177-phosphorylation. In addition, a later increase of eNOS expression is found. With supraphysiological amounts of T or DHT the induction of NO synthesis is lost. A concentration-related increase of t-PA expression starting from physiological concentrations of T or DHT is found, while PAI-1 is augmented only with higher doses. While DHT exerts these actions through androgen receptors (AR), T acts in part through aromatase dependent conversion to 17â-estradiol. Ovariectomy is associated with significant changes in eNOS, t-PA and PAI-1 expression in the aorta of Wistar rats and T and DHT result in modifications on eNOS, PAI-1 and t-PA that are in line with the in vitro experiments. In conclusion, T and DHT act on endothelial cells through AR or via conversion to estradiol. Physiological, but not higher amounts are associated with enhanced NO synthesis and an increased t- PA/PAI-1 ratio. These findings are useful to understand the impact of androgens in ageing individuals.In conclusion, T and DHT act on endothelial cells through AR or via conversion to estradiol. Physiological, but not higher amounts are associated with enhanced NO synthesis and an increased t- PA/PAI-1 ratio. These findings are useful to understand the impact of androgens in ageing individuals.1177-phosphorylation. In addition, a later increase of eNOS expression is found. With supraphysiological amounts of T or DHT the induction of NO synthesis is lost. A concentrationrelated increase of t-PA expression starting from physiological concentrations of T or DHT is found, while PAI-1 is augmented only with higher doses. While DHT exerts these actions through androgen receptors (AR), T acts in part through aromatase-dependent conversion to 17â-estradiol. Ovariectomy is associated with significant changes in eNOS, t-PA and PAI-1 expression in the aorta of Wistar rats and T and DHT result in modifications on eNOS, PAI-1 and t-PA that are in line with the in vitro experiments. In conclusion, T and DHT act on endothelial cells through AR or via conversion to estradiol. Physiological, but not higher amounts are associated with enhanced NO synthesis and an increased t- PA/PAI-1 ratio. These findings are useful to understand the impact of androgens in ageing individuals.