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

Chang-Peng Zhu1, Shu-Qing Liu1, Ke-Qi Wang1

  • 1Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China.

Gastroenterology
|June 21, 2024
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Summary
This summary is machine-generated.

This study shows that serotonin (5-HT) increases portal hypertension (PH) by constricting the portal vein (PV) via 5-HT receptor 1A (HTR1A). Targeting HTR1A with antagonists like alverine may treat PH.

Keywords:
5-HydroxytryptamineAlverineHTR1APortal HypertensionPortal Vein Smooth Muscle Cells

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Area of Science:

  • Hepatology
  • Vascular Biology
  • Pharmacology

Background:

  • Portal hypertension (PH) is a frequent complication of chronic liver disease.
  • Elevated peripheral 5-hydroxytryptamine (5-HT) levels are observed in cirrhotic patients.
  • The role of 5-HT receptor 1A (HTR1A) in the portal vein (PV) in PH pathogenesis is unclear.

Purpose of the Study:

  • To investigate the function and mechanism of HTR1A in the PV in the context of PH.
  • To explore HTR1A as a potential therapeutic target for PH.

Main Methods:

  • PH models were established using thioacetamide injection, bile duct ligation, or partial PV ligation.
  • HTR1A expression was analyzed using RT-PCR, in situ hybridization, and immunofluorescence.
  • The effects of 5-HT, HTR1A agonist (8-OH-DPAT), and antagonist (WAY-100635) on portal pressure (PP) were assessed via in situ intraportal infusion.
  • Htr1a-knockout and VSMC-specific Htr1a-knockout models were utilized to confirm HTR1A's role in regulating PP.

Main Results:

  • HTR1A expression was significantly upregulated in the PV of PH models and cirrhotic patients.
  • 5-HT and 8-OH-DPAT increased PP and induced isolated PV contraction, while WAY-100635 decreased PP.
  • Genetic deletion of Htr1a prevented PH development.
  • 5-HT-induced PV smooth muscle cell contraction was mediated by the cAMP pathway via HTR1A.
  • Alverine, an HTR1A antagonist, reduced PP in various PH models.

Conclusions:

  • 5-HT exacerbates PH by inducing PV contraction through HTR1A.
  • HTR1A is identified as a promising therapeutic target for PH.
  • Alverine shows potential as a clinical candidate for PH treatment.