%0 Journal Article
%T Targeting 5-Hydroxytryptamine receptor 1A in portal vein to decrease portal hypertension.
%A Zhu CP
%A Liu SQ
%A Wang KQ
%A Xiong HL
%A Aristu-Zabalza P
%A Boyer-Díaz Z
%A Feng JF
%A Song SH
%A Luo C
%A Chen WS
%A Zhang X
%A Dong WH
%A Gracia-Sancho J
%A Xie WF
%J Gastroenterology
%V 0
%N 0
%D 2024 Jun 19
%M 38906512
%F 33.883
%R 10.1053/j.gastro.2024.06.007
%X <B>OBJECTIVE: </B>Portal hypertension (PH) is one of the most frequent complications of chronic liver disease. The peripheral 5-Hydroxytryptamine (5-HT) level was increased in cirrhotic patients. We aimed to elucidate the function and mechanism of 5-HT receptor 1A (HTR1A) in portal vein (PV) on PH.<BR><B>METHODS: </B>PH models were induced by thioacetamide (TAA) injection, bile duct ligation (BDL) or partial portal vein ligation (PPVL). HTR1A expression was detected using real-time PCR, in situ hybridization and immunofluorescence staining. In situ intraportal infusion was employed to assess the effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP). Htr1a knock-out (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a knock-out (Htr1aΔVSMC) mice were utilized to confirm the regulatory role of HTR1A on PP.<BR><B>RESULTS: </B>HTR1A expression was significantly increased in the hypertensive PV of PH model rats and cirrhotic patients. Additionally, 8-OH-DPAT increased but WAY-100635 decreased PP in rats, without affecting liver fibrosis and systemic hemodynamics. Furthermore, 5-HT or 8-OH-DPAT directly induced the contraction of isolated PVs. Genetic deletion of Htr1a in rats and VSMCs-specific Htr1a knock-out in mice prevented the development of PH. Moreover, 5-HT triggered the cAMP pathway-mediated PVSMCs contraction via HTR1A in PV. We also confirmed alverine as an HTR1A antagonist and demonstrated its capacity to decrease PP in TAA-, BDL-, and PPVL-induced portal hypertensive rats.<BR><B>CONCLUSIONS: </B>Our findings reveal that 5-HT promotes PH by inducing the contraction of PV, and identify HTR1A as a promising therapeutic target for attenuating PH. As an HTR1A antagonist, alverine is expected to become a candidate for clinical PH treatment.