The effects of testosterone and dihydrotestosterone on endothelial nitric oxide synthase activity and on the expression of eNOS in human endothelial cells.

L. GOGLIA; V. TOSI; S. GARIBALDI; C. BALDACCI; S. PISANESCHI; M.S. GIRETTI; M.I. FLAMINI; A.M. SANCHEZ; A.R. GENAZZANI; T. SIMONCINI

10-13 September, Rome, Italy

Congreso; 8th ESG Congress of the European Society of Gynecology.; 2009

European Society of Gynecology

Testosterone has been considered detrimental to the cardiovascular system, however, this is controversial. In the present study, we tested the effects of testosterone (T) and its metabolite, dihydrotestosterone (DHT), on endothelial nitric oxide synthase (eNOS) activity and on nitric oxide (NO) release. In addition, the influence of these compounds on the expression of tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) was studied in cultured human umbilical endothelial cells. Our results show that at low concentrations (10-9 M), treatment with both T and DHT for 30 min rapidly increases eNOS activity as well as NO release. Flutamide blocks these actions. Intriguingly, the estrogen receptor antagonist, ICI 182,780 also inhibits eNOS activity and NO production enhanced by T. Both T and DHT induce a rapid phosphorylation of mitogen-activated protein kinase and Akt. The addition of the phosphatidylinositol-3 kinase (PI3K) inhibitor, wortmannin, and of the mitogen activated protein kinase kinase (MEK) inhibitor, PD98059, prevent T- or DHT-dependent eNOS activation and NO release, suggesting that PI3K/Akt and ERK1/2 are important mediators. However, at high concentration (10-8-10-6 M), these two compounds lead to a decreased eNOS activity and NO production. T and DHT in a low concentrations (10-9 M), enhance the expression of PAI-1 and decrease tPA expression. In higher concentrations, however, they result in opposite changes. Testosterone and DHT function differently on human endothelial cells depending on their concentration. At the lower concentration, they may be cardio protective by regulating eNOS activity, NO production and the expression of PAI-1 and tPA, while at higher concentrations, they may have deleterious effects.