Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis
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 ch...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2020-12-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.140485 |
| _version_ | 1818574791612825600 |
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| author | Akiko Nakayama Julián Albarrán-Juárez Guozheng Liang Kenneth Anthony Roquid András Iring Sarah Tonack Min Chen Oliver J. Müller Lee S. Weinstein Stefan Offermanns |
| author_facet | Akiko Nakayama Julián Albarrán-Juárez Guozheng Liang Kenneth Anthony Roquid András Iring Sarah Tonack Min Chen Oliver J. Müller Lee S. Weinstein Stefan Offermanns |
| author_sort | Akiko Nakayama |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-15T00:30:48Z |
| format | Article |
| id | doaj.art-c1ebda9a5f75409cbfaf0b5ba83c0cbb |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-15T00:30:48Z |
| publishDate | 2020-12-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-c1ebda9a5f75409cbfaf0b5ba83c0cbb2022-12-21T22:42:01ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-12-01523Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosisAkiko NakayamaJulián Albarrán-JuárezGuozheng LiangKenneth Anthony RoquidAndrás IringSarah TonackMin ChenOliver J. MüllerLee S. WeinsteinStefan OffermannsAtherosclerosis 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.https://doi.org/10.1172/jci.insight.140485InflammationVascular biology |
| spellingShingle | Akiko Nakayama Julián Albarrán-Juárez Guozheng Liang Kenneth Anthony Roquid András Iring Sarah Tonack Min Chen Oliver J. Müller Lee S. Weinstein Stefan Offermanns Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis JCI Insight Inflammation Vascular biology |
| title | Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis |
| title_full | Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis |
| title_fullStr | Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis |
| title_full_unstemmed | Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis |
| title_short | Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis |
| title_sort | disturbed flow induced gs mediated signaling protects against endothelial inflammation and atherosclerosis |
| topic | Inflammation Vascular biology |
| url | https://doi.org/10.1172/jci.insight.140485 |
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