Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure
Andras Iring, … , Lee S. Weinstein, Stefan Offermanns
Andras Iring, … , Lee S. Weinstein, Stefan Offermanns
Published June 17, 2019
Citation Information: J Clin Invest. 2019;129(7):2775-2791. https://doi.org/10.1172/JCI123825.
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Research Article Vascular biology

Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

Abstract

Hypertension is a primary risk factor for cardiovascular diseases including myocardial infarction and stroke. Major determinants of blood pressure are vasodilatory factors such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Several endothelial signaling processes mediating fluid shear stress–induced formation and release of vasodilatory factors have been described. It is, however, still poorly understood how fluid shear stress induces these endothelial responses. Here we show that the endothelial mechanosensitive cation channel PIEZO1 mediated fluid shear stress–induced release of adrenomedullin, which in turn activated its Gs-coupled receptor. The subsequent increase in cAMP levels promoted the phosphorylation of endothelial NO synthase (eNOS) at serine 633 through protein kinase A (PKA), leading to the activation of the enzyme. This Gs/PKA-mediated pathway synergized with the AKT-mediated pathways leading to eNOS phosphorylation at serine 1177. Mice with endothelium-specific deficiency of adrenomedullin, the adrenomedullin receptor, or Gαs showed reduced flow-induced eNOS activation and vasodilation and developed hypertension. Our data identify fluid shear stress–induced PIEZO1 activation as a central regulator of endothelial adrenomedullin release and establish the adrenomedullin receptor and subsequent Gs-mediated formation of cAMP as a critical endothelial mechanosignaling pathway regulating basal endothelial NO formation, vascular tone, and blood pressure.

Authors

Andras Iring, Young-June Jin, Julián Albarrán-Juárez, Mauro Siragusa, ShengPeng Wang, Péter T. Dancs, Akiko Nakayama, Sarah Tonack, Min Chen, Carsten Künne, Anna M. Sokol, Stefan Günther, Alfredo Martínez, Ingrid Fleming, Nina Wettschureck, Johannes Graumann, Lee S. Weinstein, Stefan Offermanns

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Figure 3

Endothelial Gαs is required for flow-induced vasodilation and blood pressure control.

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Endothelial Gαs is required for flow-induced vasodilation and blood pres...
(A and B) Aorta segments from WT or induced EC-Gαs-KO mice were incubated with increasing concentrations of phenylephrine (A) or were precontracted with 10 μM phenylephrine and exposed to acetylcholine (B), and vascular tension was determined (n = 5). (C) Mesenteric arteries isolated from tamoxifen-treated WT or EC-Gαs-KO mice were precontracted with 100 nM U46619 and exposed to stepwise increases in perfusion flow. Shown is the flow-induced vasodilation as a percentage of the passive vessel diameter (n = 11, WT; n = 7, EC-Gαs-KO). (D) Mean arterial blood pressure measured in conscious, freely moving WT (n = 11) and EC-Gαs-KO mice (n = 7) before, during, and after tamoxifen treatment. Bar diagrams show systolic and diastolic arterial blood pressure during 4 days before tamoxifen treatment and during the second week after induction. (E) Immuno-confocal microscopy images of aortae isolated from WT or EC-Gαs-KO mice stained with antibodies directed against eNOS, phosphorylated eNOS (S632 or S1176, green), and the endothelial marker CD31 (red). Shown is 1 of 2 independent experiments. Scale bar: 25 μm. (F) Phosphorylation of eNOS at serine 632 and 1176 in lysates from mesenteric arteries prepared from tamoxifen-treated WT and EC-Gαs-KO mice. Graphs show the densitometric evaluation (n = 3). (G) Plasma nitrate and nitrite (NOx) levels in WT (n = 8) and EC-Gαs-KO mice (n = 8) 10 days after induction. Data represent the mean ± SEM; *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, 2-way ANOVA with Bonferroni’s post hoc test (A–C), paired 2-tailed Student’s t test (D), or unpaired 2-tailed Student’s t test (F and G).