Aim of the study

This study investigated estrogen receptor (ER) subtype-specific effects on vascular hyporeactivity in cirrhotic portal hypertension (PHT), focusing on RhoA/ROCK signaling and -arrestin-2.

Material and methods

Cirrhosis and PHT were established by subcutaneous injection of CCl₄. Cirrhotic rats were administered three ER subtype selective agonists (PPT [ER], DPN [ER], G1 [GPER]) or -estradiol (E2) alone or in combination with selective antagonists (MPP [ER], PHTPP [ER], G15 [GPER]). Portal pressure and mesenteric arteriolar reactivity to norepinephrine were assessed. Protein expression was analyzed by immunoblotting.

Results

In cirrhotic rats, portal pressure was significantly elevated, and the dose-response curve of mesenteric arterioles to norepinephrine (NE) exhibited a rightward shift with reduced amplitude. Compared to cirrhotic rats, the CCl₄ + E2 and CCl₄ + DPN groups exhibited significantly reduced portal pressure and a leftward shift in the dose-response curve. The portal pressure was higher and the curve exhibited a rightward shift with reduced amplitude in group CCl₄ + E2 + PHTPP, compare to group CCl₄ + E2. Both portal pressure and the dose-response curve in the CCl₄ + E2 + MPP and CCl₄ + E2 + G15 groups remained comparable to the CCl₄ + E2 group. Immunoblotting and densitometric analysis revealed that the intensity of -arrestin-2 expression increased when cirrhosis and PHT developed. Compared with the CCl₄ group, the intensity in the CCl₄ + E2, CCl₄ + DPN, CCl₄ + E2 + MPP, and CCl₄ + E2 + G15 groups decreased, while that in the CCl₄ + PPT, CCl₄ + G1, and CCl₄ + E2 + PHTPP groups remained unchanged. No significant changes occurred in 1-AR, RhoA, ROCK-1, or moesin expression across groups.

Conclusions

ER activation improves vascular hyporesponsiveness in cirrhosis by modulating -arrestin-2, suggesting that ER may represent a novel therapeutic target for cirrhosis and PHT.