Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Inflammation Vascular biology

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

  • Text
  • PDF
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

×

Figure 3

Induced loss of endothelial Gαs results in increased endothelial inflammation and atherosclerotic plaque formation.

Options: View larger image (or click on image) Download as PowerPoint
Induced loss of endothelial Gαs results in increased endothelial inflamm...
(A) Cross-sections of the inner curvatures of aortic arches of control or EC-Gαs–KO mice stained with DAPI (blue) and antibodies against CCL2 or E-selectin (green) and CD31 (red). Bar diagrams show percentage of area stained by anti-CCL2 or anti–E-selectin antibodies of total endothelial cell area defined by anti-CD31 antibody staining (n = 6 animals per group; at least 3 sections were analyzed per animal). Scale bar: 25 μm. (B) Atherosclerosis-prone Ldlr-KO mice without (Ldlr-KO) or with endothelium-specific Gαs deficiency (Ldlr-KO;EC-Gαs–KO) were sham operated or underwent 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 mice per group). Scale bar: 100 μm. (C and D) Ldlr-KO or Ldlr-KO;EC-Gαs–KO mice were fed a high-fat diet for 14 weeks. (C) En face view on whole aortae stained with Oil Red O. (D) Representative images of atherosclerotic plaques observed in brachiocephalic arteries. Scale bar: 50 μm. The bar diagrams show atherosclerotic lesion area as percentage of total aorta area (C) or total arterial area (D) (n = 8, Ldlr-KO; n = 9, Ldlr-KO;EC-Gαs–KO [C]; n = 6 per genotype [D]). Data represent mean ± SEM; **P ≤ 0.01, ***P ≤ 0.001 (2-tailed Student’s t test).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts