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This work was supported by the National Natural Science Foundation of China (82030021 to Wei-Fen Xie, 81900543 to Chang-Peng Zhu, and 82200678 to Ke-Qi Wang) , the National Key R&D Program of China (2023YFC2507500 to Wei-Fen Xie) , the Instituto de Salud Carlos III (FIS PI23/00945 and DTS22/00010 to Jordi Gracia-Sancho, cofunded by the European Union) , and AGAUR-Generalitat de Catalunya (2021 SGR 01322 and 2021 PROD 00036 to Jordi Gracia-Sancho) .

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Targeting 5-Hydroxytryptamine Receptor 1A in the Portal Vein to Decrease Portal Hypertension

Publicat a:Gastroenterology. 167 (5): 993-1007 - 2024-10-01 167(5), DOI: 10.1053/j.gastro.2024.06.007

Autors: Zhu, CP; Liu, SQ; Wang, KQ; Xiong, HL; Feng, JF; Zhang, X; Xie, WF; Aristu-Zabalza, P; Boyer-Diaz, Z; Gracia-Sancho, J; Song, SH; Luo, C; Chen, WS; Dong, WH

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BACKGROUND & AIMS:Portal hypertension (PH) is one of themost frequent complications of chronic liver disease. The pe-ripheral 5-hydroxytryptamine (5-HT) level was increased incirrhotic patients. We aimed to elucidate the function andmechanism of 5-HT receptor 1A (HTR1A) in the portal vein(PV) on PH.METHODS:PH models were induced by thio-acetamide injection, bile duct ligation, or partial PV ligation.HTR1A expression was detected using real-time polymerasechain reaction, in situ hybridization, and immunofluorescencestaining. In situ intraportal infusion was used to assess theeffects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1Aantagonist WAY-100635 on portal pressure (PP).Htr1a-knockout (Htr1a(-/-)) rats and vascular smooth muscle cell(VSMC)-specificHtr1a-knockout (Htr1a(Delta VSMC)) mice were usedto confirm the regulatory role of HTR1A on PP.RESULTS:HTR1A expression was significantly increased in the hyper-tensive PV of PH model rats and cirrhotic patients. Additionally,8-OH-DPAT increased, but WAY-100635 decreased, the PP inrats without affecting liverfibrosis and systemic hemody-namics. Furthermore, 5-HT or 8-OH-DPAT directly induced thecontraction of isolated PVs. Genetic deletion ofHtr1ain ratsand VSMC-specificHtr1aknockout in mice prevented thedevelopment of PH. Moreover, 5-HT triggered adenosine 30,50-cyclic monophosphate pathway-mediated PV smooth musclecell contraction via HTR1A in the PV. We also confirmedalverine as an HTR1A antagonist and demonstrated its capacityto decrease PP in rats with thioacetamide-, bile duct ligation-,and partial PV ligation-induced PH.CONCLUSIONS:Ourfind-ings reveal that 5-HT promotes PH by inducing the contractionof the PV and identify HTR1A as a promising therapeutic targetfor attenuating PH. As an HTR1A antagonist, alverine is ex-pected to become a candidate for clinical PH treatment.

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