3 years ago

TRPV4 regulates vascular endothelial permeability during colonic inflammation in dextran sulphate sodium-induced murine colitis

Shinichi Kato, Riho Yamaba, Ken Inoue, Takuya Tsukahara, Daichi Utsumi, Kikuko Amagase, Makoto Tominaga, Kenjiro Matsumoto
Background and Purpose The transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel involved in physical sensing in various tissue types. The present study aimed to elucidate the function and expression of TRPV4 in colonic vascular endothelial cells during dextran sulphate sodium (DSS)-induced colitis. Experimental Approach The role of TRPV4 in the progression of colonic inflammation was examined in the 2 % DSS-induced murine colitis model using immunohistochemical analysis, western blotting, and Evans blue dye extrusion assay. Key Results DSS-induced colitis was significantly attenuated in TRPV4-deficient (TRPV4 KO) mice when compared to wild-type mice. Repeated intrarectal administration of GSK1016790A, a TRPV4 agonist, exacerbated the severity of DSS-induced colitis. Bone marrow transfer experiments demonstrated a dominant role of TRPV4 in non-haematopoietic cells for DSS-induced colitis. DSS treatment upregulated TRPV4 expression in the vascular endothelia of colonic mucosa and submucosa. DSS treatment increased vascular permeability, which was abolished in TRPV4 KO mice. The DSS-induced increase in vascular permeability was further enhanced by intravenous administration of GSK1016790A, which was abrogated by TRPV4 antagonist RN1734. TRPV4 was co-localised with vascular endothelial (VE)-cadherin, and VE-cadherin expression was decreased by repeated intravenous administration of GSK1016790A during colitis. Furthermore, TRPV4 activation by GSK106790A decreased VE-cadherin expression in mouse aortic endothelial cells exposed to TNF-α. Conclusion and Implications These findings indicate that TRPV4 upregulation in vascular endothelial cells contributes to the progression of colonic inflammation via the activation of vascular permeability. Thus, TRPV4 is an attractive target for the treatment of inflammatory bowel diseases.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14072

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