Estrogen receptor β activation attenuates portal hypertension and restores mesenteric vascular reactivity in cirrhotic rats via β-arrestin-2/RhoA/ROCK pathway modulation.

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 β-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 [ERα], DPN [ERβ], G1 [GPER]) or β-estradiol (E2) alone or in combination with selective antagonists (MPP [ERα], PHTPP [ERβ], 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 β-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 α1-AR, RhoA, ROCK-1, or moesin expression across groups. CONCLUSIONS: ERβ activation improves vascular hyporesponsiveness in cirrhosis by modulating β-arrestin-2, suggesting that ERβ may represent a novel therapeutic target for cirrhosis and PHT.