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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 July 1, 2019; First published June 17, 2019
Citation Information: J Clin Invest. 2019;129(7):2775-2791. https://doi.org/10.1172/JCI123825.
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Categories: Research Article Vascular biology

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

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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 5

Role of adrenomedullin in flow-induced eNOS regulation.

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Role of adrenomedullin in flow-induced eNOS regulation.
(A) BAECs were t...
(A) BAECs were treated with adrenomedullin (ADM, 10 nM, 5 minutes), calcitonin gene–related peptide (CGRP; 10 nM, 10 minutes), or adrenomedullin-2 (ADM2, 1 nM, 3 minutes), and phosphorylation of eNOS S635 was determined by immunoblotting. Bar diagram shows the densitometric evaluation (n = 3). (B–D and F–H) BAECs (B, C, and F–H) or HAECs (D) were transfected with scrambled (control) siRNA or siRNA directed against Gαs, CALCRL, eNOS, or ADM as indicated. In D, eNOS WT or the eNOS phospho-site mutants S1177A and S633A were expressed by lentiviral transduction. Cells were treated with adrenomedullin (ADM, 10 nM, 5 minutes [B] or 30 minutes [D]) or adrenomedullin-2 (ADM2, 1 nM, 3 minutes, C) or were exposed to 15 dyn/cm2 for 30 minutes or for the indicated time periods (F–H). Phosphorylation of eNOS at serine 635 and serine 1179 was determined by immunoblotting (B, C, and F). Intracellular cAMP concentration (n = 7, control; n = 6, CALCRL; n = 8, ADM) (G) or nitrate and nitrite concentration in the cell culture medium (n = 6 [D]; n = 13, control; n = 4, CALCRL; n = 5, ADM [H]) was determined. Bar diagrams in B, C, and F show densitometric evaluation of immunoblots (n = 3). (E) Expression of ADM, CGRP (CALCA), ADM2, and RAMP1–3 RNA in BAECs and HUVECs (n = 4). Data represent the mean ± SEM; *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.00, 2-way ANOVA with Bonferroni’s post hoc test (A–D, G, and H) or 1-way ANOVA with Tukey’s post hoc test (F).
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