Transient receptor potential vanilloid 4 channel regulates vascular endothelial permeability during colonic inflammation in dextran sulphate sodium-induced murine colitis

BACKGROUND AND PURPOSE The transient receptor potential vanilloid 4 (TRPV4) channel is a non-selective cation channel involved in physical sensing in various tissue types. The present study aimed to elucidate the function and expression of TRPV4 channels in colonic vascular endothelial cells during dextran sulphate sodium (DSS)-induced colitis. EXPERIMENTAL APPROACH The role of TRPV4 channels in the progression of colonic inflammation was examined in a murine DSS-induced 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) as 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 the important role of TRPV4 in non-haematopoietic cells for DSS-induced colitis. DSS treatment up-regulated TRPV4 expression in the vascular endothelia of colonic mucosa and submucosa. DSS treatment increased vascular permeability, which was abolished in TRPV4 KO mice. This DSS-induced increase in vascular permeability was further enhanced by i.v. administration of GSK1016790A, and this effect was abolished by the TRPV4 antagonist RN1734. TRPV4 was co-localized with vascular endothelial (VE)-cadherin, and VE-cadherin expression was decreased by repeated i.v. administration of GSK1016790A during colitis. Furthermore, GSK106790A decreased VE-cadherin expression in mouse aortic endothelial cells exposed to TNF-alpha. CONCLUSION AND IMPLICATIONS These findings indicate that an up-regulation of TRPV4 channels in vascular endothelial cells contributes to the progression of colonic inflammation by increasing vascular permeability. Thus, TRPV4 is an attractive target for the treatment of inflammatory bowel diseases.