Downregulation of endothelial transient receptor potential vanilloid type 4 channel underlines impaired endothelial nitric oxide-mediated relaxation in the mesenteric arteries of hypertensive rats

Abstract

The endothelium contributes to the maintenance of vasodilator tone by releasing endothelium-derived relaxing factors, including nitric oxide (NO). In hypertension, endothelial nitric oxide synthase (eNOS) produces less NO and could be one of the contributing factors to the increased peripheral vascular resistance. Agonist-induced Ca(2+) entry is essential for the activation of eNOS. The transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca(2+)-permeant cation channel, is expressed in the endothelial cells and involved in the regulation of vascular tone. The present study aimed to investigate the role of TRPV4 channel in endothelium-dependent NO-mediated relaxation of the resistance artery in hypertensive rats. Using a wire myograph, relaxation response to the TRPV4 activator, 4alpha-phorbol-12,13-didecanoate (4alphaPDD) was assessed in mesenteric arteries obtained from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs). Compared to WKY, SHR demonstrated a significantly attenuated 4alphaPDD-induced endothelium-dependent NO-mediated relaxation. Immunohistochemical analysis revealed positive staining for TRPV4 in the endothelium of mesenteric artery sections in both WKY and SHR. Furthermore, TRPV4 mRNA and protein expressions in SHR were significantly lower than their expression levels in WKY rats. We conclude that 4alphaPDD-induced endothelium-dependent NO-mediated vasorelaxation is reduced in SHR and downregulation of TRPV4 could be one of the contributing mechanisms.

The Transient Receptor Potential Vanilloid 4 Channel and Cardiovascular Disease Risk Factors

“…In accord with our findings, Boudaka et al (2019) reported decreased expression of endothelial TRPV4 and impaired endothelium-dependent vasorelaxation in second-order branches of the mesenteric arteries of 10- to 12-week-old SHR, although some disparities exist between the two studies. While the downregulation of endothelial TRPV4 led to a loss of NO in the Boudaka et al (2019) study, the downregulation of endothelial TRPV4 led to a loss of EDH in our study. The reason for the disparity is not clear, but it might be related to the differences in strain, age, or vessel diameter used.…”

Reduced Post-ischemic Brain Injury in Transient Receptor Potential Vanilloid 4 Knockout Mice

“…Dilation of leptomeningeal arteries occurs as early as 6 h after pMCAO via increased phosphorylation of endothelial nitric oxide synthase (eNOS) in response to shear stress (Iwasawa et al, 2018). Meanwhile, Trpv4 −/− mice exhibited loss of shear stress-induced vasodilatation of the carotid artery (Hartmannsgruber et al, 2007), and endothelial downregulation of TRPV4 was shown to contribute to impairment of eNOS-mediated relaxation of the mesenteric artery (Boudaka et al, 2019). These findings suggest that TRPV4 deficiency may exacerbate ischemic brain injury through impairment of acute collateral development in cases of recanalization failure, such as the pMCAO model.…”

Transient receptor potential vanilloid (TRPV) channels: Basal properties and physiological potential

“…In INS-1E pancreatic β cells, 4α-PDD treatment increases intracellular Ca 2+ levels and enhances glucose-stimulated insulin secretion (Skrzypski et al 2013). Furthermore, in rodents, 4α-PDD induces endothelial-dependent NO-mediated relaxation in the mesenteric arteries (Boudaka et al 2019). 4α-PDD treatment elicits the dilation of mesenteric arteries in aged rats by increasing intracellular Ca 2+ levels (Du et al 2016).…”