| First Author | Nakayama A | Year | 2020 |
| Journal | JCI Insight | Volume | 5 |
| Issue | 23 | PubMed ID | 33268595 |
| Mgi Jnum | J:312297 | Mgi Id | MGI:6741417 |
| Doi | 10.1172/jci.insight.140485 | Citation | Nakayama A, et al. (2020) Disturbed flow-induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis. JCI Insight 5(23) |
| abstractText | 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-kappaB 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 Galphas, the alpha 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 Galphas, 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. |
