<<Il>> ruolo del GPER nelle arterie uterine e mesenteriche in gravidanza

Abstract

Low uteroplacental blood flow has been implicated as a cause of pregnancy hypertension and intrauterine fetal growth retardation. A successful pregnancy outcome requires a sufficient uteroplacental blood flow, which increases of many fold compared to the non pregnant levels. This significant increase is achieved in part by vasodilation of the uterine vasculature because pregnancy induces a physiological remodelling of the maternal uterine circulation. Estrogen may contribute to this effect although the mechanisms involved remain unclear. It is known that estrogen receptor-α and estrogen receptor-β in the uterine vascular endothelium are both functionally implicated in the regulation of the uterine blood flow but so far nothing is known about the novel G-protein coupled estrogen receptor (GPER) in the uterine vasculature. GPER has been identified in many vascular bed exerting its potential vasorelaxing effect. The aim of this study was to investigate the function of GPER in the regulation of the uterine vascular tone during pregnancy. Experiments were carried out on mesenteric arterioles and uterine radial arteries isolated from both non-pregnant (NP) and age-matched pregnant (P) Sprague Dawley rats to compare reproductive and systemic vasculature effect. Arterial segments were pressurized to 50 mmHg in the pressure myography, preconstricted of 40% with phenylephrine and then incubated with incremental doses (10-12-10-6 M) of the specific GPER agonist, G-1. A dose-response curve was obtained for G-1 in the 1 pM – 1 μM range with a maximum vasodilation of uterine arteries of 97,8 ± 2,5% in P vs 66,5 ± 3,7% in NP, p<0.001. G-1 vasorelaxing effect was similar in pregnant (45,5 ± 6,1%) and non-pregnant (53,6 ± 2,3%) mesenteric arteries. Pregnancy induced a significantly higher G-1 vasodilation only in uterine artery and its protein expression was also increased. G-1 effect was significantly reduced by the GPER antagonist, G-15. The NOS inhibitors, L-NAME+L-NNA or endothelium removal reduced the G-1 induced relaxation of uterine artery, suggesting an endothelium-dependent mechanism, involving cGMP pathway but not BKca channels. Immunohistochemistry revealed the GPER expression in the main uterine artery of both eNOS-/- and wild type pregnant mice. This receptor was functionally activated in a dose response manner with a significant less effect in knock out mice, showing the relevance of the NO in GPER pathway. GPER is also present in human chorionic plate arteries and its activation induces a slight vasodilation. These results demonstrate for the first time that GPER may have a role in regulating vascular tone, placental perfusion and normal fetal development, suggesting a potential therapeutic target in pregnant diseases.