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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) .

Analysis of institutional authors

Aristu-Zabalza, PeioAuthorGracia-Sancho, JordiCorresponding Author

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October 6, 2024
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Targeting 5-Hydroxytryptamine Receptor 1A in the Portal Vein to Decrease Portal Hypertension

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

Authors: 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

Affiliations

Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Key Lab Receptor Res,State Key Lab Drug Res, Shanghai, Peoples R China - Author
IDIBAPS Hosp Clin Barcelona, CIBEREHD, Liver Vasc Biol Res Grp, Barcelona, Spain - Author
Naval Med Univ, Changzheng Hosp, Dept Gastroenterol, 415 Fengyang Rd, Shanghai, Peoples R China - Author
Naval Med Univ, Changzheng Hosp, Dept Intervent Radiol, 415 Fengyang Rd, Shanghai, Peoples R China - Author
Naval Med Univ, Changzheng Hosp, Dept Pharm, Shanghai, Peoples R China - Author
Naval Med Univ, Changzheng Hosp, Organ Transplantat Ctr, Shanghai, Peoples R China - Author
Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China - Author
Univ Bern, Dept BioMed Res, Hepatol, Bern, Switzerland - Author
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Abstract

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.

Keywords

2 dipropylamino 8 hydroxytetralin5-hydroxytryptamine8-hydroxy-2-(di-n-propylamino)tetralinAlverinAlverineAlverine citrateAnimalAnimalsC57bl mouseCirrhosisCyclic ampDisease modelDisease models, animalDrug effectEtiologyExperimental liver cirrhosisGeneticsHtr1aHuman tissueHumansHypertension, portalImmunofluorescenceImmunofluorescence assayImmunohistochemistryIn situ hybridizationInternational unionIntraportal drug administrationIrritable-bowel-syndromeKetanseriKnockout mouseLigationLight-chain kinaseLiver cirrhosisLiver cirrhosis, experimentalLiver fibrosisLiver tissueMaleMechanismsMessenger rnaMetabolismMiceMice, inbred c57blMice, knockoutMouseMuscle fiber contractionMuscle, smooth, vascularMyocytes, smooth muscleN [2 [4 (2 methoxyphenyl) 1 piperazinyl]ethyl] n (2 pyridyl)cyclohexanecarboxamideN-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-n-(2-pyridinyl)cyclohexanecarboxamideNonhumanPathologyPathophysiologyPhPhosphorylationPiperazine derivativePiperazinesPortal hypertensionPortal pressurePortal veinPortal vein blood pressurePortal vein smooth muscle cellsPressurePyridine derivativePyridinesRatRatsRats, sprague-dawleyReal time polymerase chain reactionReceptor, serotonin, 5-ht1aSerotoninSerotonin 1 agonistSerotonin 1 receptorSerotonin 5-ht1 receptor agonistsSerotonin 5-ht1 receptor antagonistsSignal transductionSmooth muscle cellSprague dawley ratThioacetamideVascular smooth muscleVascular smooth muscle cellVascular smooth-muscleVenous smooth muscleWestern blotting

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal GASTROENTEROLOGY due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 4/143, thus managing to position itself as a Q1 (Primer Cuartil), in the category Gastroenterology & Hepatology. Notably, the journal is positioned above the 90th percentile.

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-16:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 6.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 13 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 0.5.
  • The number of mentions on the social network Facebook: 2 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: China; Switzerland.

the author responsible for correspondence tasks has been Gracia Sancho, Jordi.