Comparative study on the effects of testosterone, estradiol and progesterone on prostanoid production by human endothelial cells

C Hermenegildo1,2, D Perez-Cremades2, N Martinez-Gil2, M de Lazaro2, C Bueno-Beti2, S Novella2,1. 1University of Valencia, Dep. Physiology, Spain, 2Hospital Clinico Valencia, Research Unit - INCLIVA, Spain

Endothelium is a target for different sex steroids, which include estrogens, progestagens and androgens. The main estrogen, estradiol, act in the endothelium to promote vasodilation through a release of several compounds, including synthesis of prostanoids, products of arachidonic acid metabolism. Two main prostanoids play an essential role in vascular physiology: thromboxane A2 (TXA2), which exhibits a proaggregant and vasoconstrictor profile, and prostacyclin (PGI2), a potent vasodilator. Nevertheless, the effects of other steroids, such as progesterone or testosterone on endothelial cell production of prostanoids are much less studied.

Our aim was to compare the effect of main steroids on PGI2 and TXA2 production by cultured human umbilical vein endothelial cells (HUVEC) and to study the role of sex steroid receptors on the balance PGI2/TXA2.

HUVEC were exposed to different physiological (1-10 nM) concentrations of estradiol, progesterone and testosterone for 24 hours. In some experiments, antagonists for estrogen receptor (ER) (ICI182780, 1μM), progesterone receptor (RU-486, 1μM) or testosterone receptor (Flutamide, 1μM) were used to confirm the contribution of steroid receptors. PGI2 and TXA2 production was measured by ELISA. ANOVA test and then Bonferroni’s test were performed. Data are expressed as a percentage of control values, and are mean ± SEM.

As demonstrated earlier, estradiol dose-dependent increased PGI2 production, up to 180 %, at all the tested concentrations (p < 0.05 vs. control) without affecting TXA2 production. Progesterone exerted a similar effect on PGI2 production, by increasing it to 155 % at 10 nM (p < 0.01 vs. control), along with a slight (15 %), but significant reduction of TXA2 (p < 0.05 vs. control). Testosterone was able to slightly reduce TXA2 production up to 80 % of control values (p < 0.05) without affecting PGI2 production. All these effects were mediated through the different steroid receptors since were abolished in the presence of their antagonists (p < 0.05 vs. the effect obtained with the steroid alone).

In conclusion, estradiol, progesterone and testosterone, acting through their specific steroid receptors, are able to modify the balance of PGI2/TXA2 production in human endothelial cells.