title: Characterization of blood pressure and endothelial function in TRPV4-deficient mice with l-NAME- and angiotensin II-induced hypertension.
abstract: Transient receptor potential vanilloid type 4 (TRPV4) is an endothelial Ca(2+) entry channel contributing to endothelium-mediated dilation in conduit and resistance arteries. We investigated the role of TRPV4 in the regulation of blood pressure and endothelial function under hypertensive conditions. TRPV4-deficient (TRPV4(-/-)) and wild-type (WT) control mice were given l-NAME (0.5 g/L) in drinking water for 7 days or subcutaneously infused with angiotensin (Ang) II (600 ng/kg per minute) for 14 days, and blood pressure measured by radiotelemetry. TRPV4(-/-) mice had a lower baseline mean arterial pressure (MAP) (12-h daytime MAP, 94 ± 2 vs. 99 ± 2 mmHg in WT controls). l-NAME treatment induced a slightly greater increase in MAP in TRPV4(-/-) mice (day 7, 13 ± 4%) compared to WT controls (6 ± 2%), but Ang II-induced increases in MAP were similar in TRPV4(-/-) and WT mice (day 14, 53 ± 6% and 37 ± 11%, respectively, P < 0.05). Chronic infusion of WT mice with Ang II reduced both acetylcholine (ACh)-induced dilation (dilation to 10(-5) mol/L ACh, 71 ± 5% vs. 92 ± 2% of controls) and the TRPV4 agonist GSK1016790A-induced dilation of small mesenteric arteries (10(-8) mol/L GSK1016790A, 14 ± 5% vs. 77 ± 7% of controls). However, Ang II treatment did not affect ACh dilation in TRPV4(-/-) mice. Mechanistically, Ang II did not significantly alter either TRPV4 total protein expression in mesenteric arteries or TRPV4 agonist-induced Ca(2+) response in mesenteric endothelial cells in situ. These results suggest that TRPV4 channels play a minor role in blood pressure regulation in l-NAME- but not Ang II-induced hypertension, but may be importantly involved in Ang II-induced endothelial dysfunction.
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin ; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nishijima
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin ; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Hayley
authors.initials: H
authors.lastname: Lund
authors.affiliation: Department of Pharmacology, Jichi Medical University, Tochigi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: David L
authors.initials: DL
authors.lastname: Mattson
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin ; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: David X
authors.initials: DX
authors.lastname: Zhang
keywords: Endothelium; Hypertension; TRPV4; endothelium‐derived hyperpolarizing factor; mesenteric arteries; nitric oxide
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