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Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis
Akiko Nakayama, … , Lee S. Weinstein, Stefan Offermanns
Akiko Nakayama, … , Lee S. Weinstein, Stefan Offermanns
Published December 3, 2020
Citation Information: JCI Insight. 2020;5(23):e140485. https://doi.org/10.1172/jci.insight.140485.
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Research Article Inflammation Vascular biology

Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis

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Abstract

Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor–like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow–induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis.

Authors

Akiko Nakayama, Julián Albarrán-Juárez, Guozheng Liang, Kenneth Anthony Roquid, András Iring, Sarah Tonack, Min Chen, Oliver J. Müller, Lee S. Weinstein, Stefan Offermanns

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Figure 4

Adrenomedullin is released in response to oscillatory flow and activate antiinflammatory signaling though its receptor CALCRL.

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Adrenomedullin is released in response to oscillatory flow and activate ...
(A and B) Confluent BAECs were transfected with control siRNA (control) or siRNA directed against Gαs, GPR146, or CALCRL. p65 and CREB phosphorylation before or after oscillatory (osc.) flow induction (15 minutes) were determined. Bar diagrams show the statistical evaluation of immunoblots (n = 3 independent experiments). (C) Confluent BAECs were exposed to osc. flow for the indicated time periods. Thereafter, adrenomedullin concentration in the cell culture medium was determined (n = 3 independent experiments). (D and E) Control, Gαs-knockdown, or adrenomedullin-knockdown (ADM-knockdown) BAECs were exposed to osc. flow, and p65 phosphorylation was determined by immunoblotting. Bar diagrams show the statistical evaluation of immunoblots (n = 4 independent experiments). Data represent mean ± SD; *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 (2-way ANOVA and Bonferroni’s post hoc test [A, B, D, and E] and 1-way ANOVA and Tukey’s post hoc test [C]).

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