TY - JOUR AU - Nakayama, Akiko AU - Albarrán-Juárez, Julián AU - Liang, Guozheng AU - Roquid, Kenneth Anthony AU - Iring, András AU - Tonack, Sarah AU - Chen, Min AU - Müller, Oliver J. AU - Weinstein, Lee S. AU - Offermanns, Stefan T1 - Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis PY - 2020/12/03/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.140485 VL - 5 IS - 23 UR - https://doi.org/10.1172/jci.insight.140485 PB - The American Society for Clinical Investigation ER -