Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis
Akiko Nakayama, Julián Albarrán-Juárez, Guozheng Liang, Kenneth Anthony Roquid, András Iring, Sarah Tonack, Min Chen, Oliver J. Müller, Lee S. Weinstein, Stefan Offermanns
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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Research Article Inflammation Vascular biology

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

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 5

Loss of endothelial ADM and its receptor CALCRL results in increased endothelial inflammation and atherosclerotic plaque formation.

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Loss of endothelial ADM and its receptor CALCRL results in increased end...
(A) Cross-sections of the inner curvatures of aortic arches of control and EC-CALCRL–KO mice stained with DAPI (blue) and antibodies against CCL2 (green), E-selectin (green), or CD31 (red). Bar diagrams show percentage of area stained by anti-CCL2 or anti–E-selectin antibodies of total endothelial cell area stained by anti-CD31 antibody (n = 6 mice per group). Scale bar: 25 μm. (B and C) Atherosclerosis-prone Ldlr-KO mice without (Ldlr-KO) or with induced endothelium-specific deficiency of CALCRL (Ldlr-KO;EC-CALCRL–KO) were fed a high-fat diet for 14 weeks. (B) Representative images of Oil Red O–stained brachiocephalic artery. Plaque area was quantified as percentage of total aortic area (n = 6 mice per group). (C) En face view on atherosclerotic lesions of aortae stained with Oil Red O (n = 7, Ldlr-KO; n = 8, Ldlr-KO;EC-CALCRL–KO). Scale bar: 200 μm. (D) Control or EC-Adm–KO mice were injected with AAV-PCSK9 or with AAV-Luc i.v. 1 week before partial carotid artery ligation. Two weeks after the ligation, serial sections were made through the entire carotid arteries and stained with elastic stain (n = 6, control; n = 8, EC-ADM KO). Scale bar: 100 μm. Data represent mean ± SEM; **P ≤ 0.01, ***P ≤ 0.001 (2-tailed Student’s t test).