The transient receptor potential vanilloid 4 (TRPV4) ion channel mediates protease activated receptor 1 (PAR1)-induced vascular hyperpermeability

Scott Peng, Megan S. Grace, Arisbel B. Gondin, Jeffri S. Retamal, Larissa Dill, William Darby, Nigel W. Bunnett, Fe C. Abogadie, Simona E. Carbone, Tara Tigani, Thomas P. Davis, Daniel P. Poole, Nicholas A. Veldhuis, Peter McIntyre

Research output: Contribution to journalArticle

Abstract

Endothelial barrier disruption is a hallmark of tissue injury, edema, and inflammation. Vascular endothelial cells express the G protein-coupled receptor (GPCR) protease acctivated receptor 1 (PAR1) and the ion channel transient receptor potential vanilloid 4 (TRPV4), and these signaling proteins are known to respond to inflammatory conditions and promote edema through remodeling of cell–cell junctions and modulation of endothelial barriers. It has previously been established that signaling initiated by the related protease activated receptor 2 (PAR2) is enhanced by TRPV4 in sensory neurons and that this functional interaction plays a critical role in the development of neurogenic inflammation and nociception. Here, we investigated the PAR1–TRPV4 axis, to determine if TRPV4 plays a similar role in the control of edema mediated by thrombin-induced signaling. Using Evans Blue permeation and retention as an indication of increased vascular permeability in vivo, we showed that TRPV4 contributes to PAR1-induced vascular hyperpermeability in the airways and upper gastrointestinal tract of mice. TRPV4 contributes to sustained PAR1-induced Ca2+ signaling in recombinant cell systems and to PAR1-dependent endothelial junction remodeling in vitro. This study supports the role of GPCR–TRP channel functional interactions in inflammatory-associated changes to vascular function and indicates that TRPV4 is a signaling effector for multiple PAR family members.

Original languageEnglish (US)
Pages (from-to)1057-1067
Number of pages11
JournalLaboratory Investigation
Volume100
Issue number8
DOIs
StatePublished - Aug 1 2020

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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    Peng, S., Grace, M. S., Gondin, A. B., Retamal, J. S., Dill, L., Darby, W., Bunnett, N. W., Abogadie, F. C., Carbone, S. E., Tigani, T., Davis, T. P., Poole, D. P., Veldhuis, N. A., & McIntyre, P. (2020). The transient receptor potential vanilloid 4 (TRPV4) ion channel mediates protease activated receptor 1 (PAR1)-induced vascular hyperpermeability. Laboratory Investigation, 100(8), 1057-1067. https://doi.org/10.1038/s41374-020-0430-7