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Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release
ShengPeng Wang, … , Nina Wettschureck, Stefan Offermanns
ShengPeng Wang, … , Nina Wettschureck, Stefan Offermanns
Published October 31, 2016
Citation Information: J Clin Invest. 2016;126(12):4527-4536. https://doi.org/10.1172/JCI87343.
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Research Article Vascular biology Article has an altmetric score of 36

Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release

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Abstract

Arterial blood pressure is controlled by vasodilatory factors such as nitric oxide (NO) that are released from the endothelium under the influence of fluid shear stress exerted by flowing blood. Flow-induced endothelial release of ATP and subsequent activation of Gq/G11–coupled purinergic P2Y2 receptors have been shown to mediate fluid shear stress–induced stimulation of NO formation. However, the mechanism by which fluid shear stress initiates these processes is unclear. Here, we have shown that the endothelial mechanosensitive cation channel PIEZO1 is required for flow-induced ATP release and subsequent P2Y2/Gq/G11–mediated activation of downstream signaling that results in phosphorylation and activation of AKT and endothelial NOS. We also demonstrated that PIEZO1-dependent ATP release is mediated in part by pannexin channels. The PIEZO1 activator Yoda1 mimicked the effect of fluid shear stress on endothelial cells and induced vasorelaxation in a PIEZO1-dependent manner. Furthermore, mice with induced endothelium-specific PIEZO1 deficiency lost the ability to induce NO formation and vasodilation in response to flow and consequently developed hypertension. Together, our data demonstrate that PIEZO1 is required for the regulation of NO formation, vascular tone, and blood pressure.

Authors

ShengPeng Wang, Ramesh Chennupati, Harmandeep Kaur, Andras Iring, Nina Wettschureck, Stefan Offermanns

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Figure 5

Endothelial PIEZO1 is required for flow-induced vasodilation.

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Endothelial PIEZO1 is required for flow-induced vasodilation.
(A) Effect...
(A) Effect of a stepwise increase in perfusion flow on the diameter of mesenteric arteries from tamoxifen-treated WT mice or EC-PIEZO1-KO mice precontracted with 100 nM of the thromboxane A2 analog U46619. After flow was stopped, 10 μM acetylcholine (ACh) was added. Right panel: Flow-induced vasorelaxation as percentage of the passive vessel diameter (n = 6, WT; n = 7, EC-PIEZO1-KO). (B) Effect of acetylcholine and phenylephrine on the tension of mesenteric artery stripes from WT (n = 5) and EC-PIEZO1-KO animals (n = 5). (C–E) Effect of Yoda1 at the indicated concentration on the diameter of mesenteric arteries precontracted by U46619 (C and D) or by induction of myogenic tone (E) from WT (n = 4), EC-PIEZO1-KO (n = 4), EC-q/11-KO (n = 3), EC-P2Y2-KO (n = 3), or EC-PANX1/2-KO (n = 3) mice. Vessels were prepared 7–10 days after tamoxifen-dependent induction. Shown are means ± SEM. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 (2-way ANOVA and Bonferroni’s post-hoc test).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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