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

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

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 1

PIEZO1 mediates endothelial response to fluid shear stress in vitro.

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PIEZO1 mediates endothelial response to fluid shear stress in vitro. HUA...
HUAECs were transfected with scrambled (control) siRNA or siRNA directed against PIEZO1 as described in Methods. (A) Fluo-4–loaded HUAECs (n = 22, control; n = 29, PIEZO1 knockdown; 3 independent experiments) were exposed to the indicated shear forces, and [Ca2+]i was determined as fluorescence intensity (RFU, relative fluorescence units). Bar diagrams show areas under the curve (AUC). Shown are means ± SEM; ***P ≤ 0.001 (2-tailed Student’s t test). (B–E) HUAECs (n = 3) were exposed to fluid shear (15 dyn/cm2) for 5 minutes in B and D or for the indicated time periods. For determination of Src activation, 15 seconds of shear was applied. AKT, eNOS, and Src activation (B and D) was determined by Western blotting for phosphorylated AKT, eNOS, and Src kinases and total AKT, eNOS, and Src. (C) Nitrate concentration in the cell medium. PECAM-1 and VEGFR2 activation (D) was determined by immunoprecipitation and Western blotting for tyrosine phosphorylated PECAM-1 and VEGFR2. Knockdown of PIEZO1 was verified by anti-PIEZO1 immunoblotting. Bar diagrams show the densitometric evaluation. (E) Concentration of ATP in the supernatant of HUAECs. Shown are means ± SEM; *P ≤ 0.05; **P ≤ 0.01 (2-way ANOVA and Bonferroni’s post hoc test).