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Serotonin-induced vascular permeability is mediated by transient receptor potential vanilloid 4 in the airways and upper gastrointestinal tract of mice.
Retamal, Jeffri S; Grace, Megan S; Dill, Larissa K; Ramirez-Garcia, Paulina; Peng, Scott; Gondin, Arisbel B; Bennetts, Felix; Alvi, Sadia; Rajasekhar, Pradeep; Almazi, Juhura G; Carbone, Simona E; Bunnett, Nigel W; Davis, Thomas P; Veldhuis, Nicholas A; Poole, Daniel P; McIntyre, Peter.
Afiliación
  • Retamal JS; Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
  • Grace MS; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia.
  • Dill LK; School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.
  • Ramirez-Garcia P; Department of Physiology, School of Medicine Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
  • Peng S; Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
  • Gondin AB; School of Clinical Medicine, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Bennetts F; School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.
  • Alvi S; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
  • Rajasekhar P; Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
  • Almazi JG; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia.
  • Carbone SE; Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
  • Bunnett NW; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia.
  • Davis TP; Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
  • Veldhuis NA; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia.
  • Poole DP; Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
  • McIntyre P; Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
Lab Invest ; 101(7): 851-864, 2021 07.
Article en En | MEDLINE | ID: mdl-33859334
Endothelial and epithelial cells form physical barriers that modulate the exchange of fluid and molecules. The integrity of these barriers can be influenced by signaling through G protein-coupled receptors (GPCRs) and ion channels. Serotonin (5-HT) is an important vasoactive mediator of tissue edema and inflammation. However, the mechanisms that drive 5-HT-induced plasma extravasation are poorly defined. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an established enhancer of signaling by GPCRs that promote inflammation and endothelial barrier disruption. Here, we investigated the role of TRPV4 in 5-HT-induced plasma extravasation using pharmacological and genetic approaches. Activation of either TRPV4 or 5-HT receptors promoted significant plasma extravasation in the airway and upper gastrointestinal tract of mice. 5-HT-mediated extravasation was significantly reduced by pharmacological inhibition of the 5-HT2A receptor subtype, or with antagonism or deletion of TRPV4, consistent with functional interaction between 5-HT receptors and TRPV4. Inhibition of receptors for the neuropeptides substance P (SP) or calcitonin gene-related peptide (CGRP) diminished 5-HT-induced plasma extravasation. Supporting studies assessing treatment of HUVEC with 5-HT, CGRP, or SP was associated with ERK phosphorylation. Exposure to the TRPV4 activator GSK1016790A, but not 5-HT, increased intracellular Ca2+ in these cells. However, 5-HT pre-treatment enhanced GSK1016790A-mediated Ca2+ signaling, consistent with sensitization of TRPV4. The functional interaction was further characterized in HEK293 cells expressing 5-HT2A to reveal that TRPV4 enhances the duration of 5-HT-evoked Ca2+ signaling through a PLA2 and PKC-dependent mechanism. In summary, this study demonstrates that TRPV4 contributes to 5-HT2A-induced plasma extravasation in the airways and upper GI tract, with evidence supporting a mechanism of action involving SP and CGRP release.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Permeabilidad Capilar / Serotonina / Tracto Gastrointestinal Superior / Canales Catiónicos TRPV / Pulmón Límite: Animals / Humans / Male Idioma: En Revista: Lab Invest Año: 2021 Tipo del documento: Article País de afiliación: Australia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Permeabilidad Capilar / Serotonina / Tracto Gastrointestinal Superior / Canales Catiónicos TRPV / Pulmón Límite: Animals / Humans / Male Idioma: En Revista: Lab Invest Año: 2021 Tipo del documento: Article País de afiliación: Australia