Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis
Flow (shear stress)-mediated dilation (FMD) of resistance arteries is a rapid endothelial response involved in tissue perfusion. FMD is reduced early in cardiovascular diseases, generating a major risk factor for atherosclerosis. As alteration of mitochondrial fusion reduces endothelial cells’ (ECs)...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/6/1078 |
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| author | Ahmad Chehaitly Anne-Laure Guihot Coralyne Proux Linda Grimaud Jade Aurrière Benoit Legouriellec Jordan Rivron Emilie Vessieres Clément Tétaud Antonio Zorzano Vincent Procaccio Françoise Joubaud Pascal Reynier Guy Lenaers Laurent Loufrani Daniel Henrion |
| author_facet | Ahmad Chehaitly Anne-Laure Guihot Coralyne Proux Linda Grimaud Jade Aurrière Benoit Legouriellec Jordan Rivron Emilie Vessieres Clément Tétaud Antonio Zorzano Vincent Procaccio Françoise Joubaud Pascal Reynier Guy Lenaers Laurent Loufrani Daniel Henrion |
| author_sort | Ahmad Chehaitly |
| collection | DOAJ |
| description | Flow (shear stress)-mediated dilation (FMD) of resistance arteries is a rapid endothelial response involved in tissue perfusion. FMD is reduced early in cardiovascular diseases, generating a major risk factor for atherosclerosis. As alteration of mitochondrial fusion reduces endothelial cells’ (ECs) sprouting and angiogenesis, we investigated its role in ECs responses to flow. Opa1 silencing reduced ECs (HUVECs) migration and flow-mediated elongation. In isolated perfused resistance arteries, FMD was reduced in <i>Opa1</i><sup>+/−</sup> mice, a model of the human disease due to Opa1 haplo-insufficiency, and in mice with an EC specific Opa1 knock-out (EC-Opa1). Reducing mitochondrial oxidative stress restored FMD in EC-Opa1 mice. In isolated perfused kidneys from EC-Opa1 mice, flow induced a greater pressure, less ATP, and more H<sub>2</sub>O<sub>2</sub> production, compared to control mice. Opa1 expression and mitochondrial length were reduced in ECs submitted in vitro to disturbed flow and in vivo in the atheroprone zone of the mouse aortic cross. Aortic lipid deposition was greater in <i>Ldlr</i><sup>−/-</sup>-<i>Opa1</i><sup>+/-</sup> and in <i>Ldlr</i><sup>−/-</sup>-EC-Opa1 mice than in control mice fed with a high-fat diet. In conclusion, we found that reduction in mitochondrial fusion in mouse ECs altered the dilator response to shear stress due to excessive superoxide production and induced greater atherosclerosis development. |
| first_indexed | 2024-03-10T00:34:17Z |
| format | Article |
| id | doaj.art-402fcf77f57b4725b909c1e8af2aedf8 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T00:34:17Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-402fcf77f57b4725b909c1e8af2aedf82023-11-23T15:19:08ZengMDPI AGAntioxidants2076-39212022-05-01116107810.3390/antiox11061078Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and AtherosclerosisAhmad Chehaitly0Anne-Laure Guihot1Coralyne Proux2Linda Grimaud3Jade Aurrière4Benoit Legouriellec5Jordan Rivron6Emilie Vessieres7Clément Tétaud8Antonio Zorzano9Vincent Procaccio10Françoise Joubaud11Pascal Reynier12Guy Lenaers13Laurent Loufrani14Daniel Henrion15MITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10–12, 08028 Barcelona, SpainMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceUniversity Hospital (CHU) of Angers, 4 rue Larrey, F-49933 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceMITOVASC Department, Team 2 (CarMe), ICAT SFR, University of Angers, 3 rue Roger Amsler, F-49500 Angers, FranceFlow (shear stress)-mediated dilation (FMD) of resistance arteries is a rapid endothelial response involved in tissue perfusion. FMD is reduced early in cardiovascular diseases, generating a major risk factor for atherosclerosis. As alteration of mitochondrial fusion reduces endothelial cells’ (ECs) sprouting and angiogenesis, we investigated its role in ECs responses to flow. Opa1 silencing reduced ECs (HUVECs) migration and flow-mediated elongation. In isolated perfused resistance arteries, FMD was reduced in <i>Opa1</i><sup>+/−</sup> mice, a model of the human disease due to Opa1 haplo-insufficiency, and in mice with an EC specific Opa1 knock-out (EC-Opa1). Reducing mitochondrial oxidative stress restored FMD in EC-Opa1 mice. In isolated perfused kidneys from EC-Opa1 mice, flow induced a greater pressure, less ATP, and more H<sub>2</sub>O<sub>2</sub> production, compared to control mice. Opa1 expression and mitochondrial length were reduced in ECs submitted in vitro to disturbed flow and in vivo in the atheroprone zone of the mouse aortic cross. Aortic lipid deposition was greater in <i>Ldlr</i><sup>−/-</sup>-<i>Opa1</i><sup>+/-</sup> and in <i>Ldlr</i><sup>−/-</sup>-EC-Opa1 mice than in control mice fed with a high-fat diet. In conclusion, we found that reduction in mitochondrial fusion in mouse ECs altered the dilator response to shear stress due to excessive superoxide production and induced greater atherosclerosis development.https://www.mdpi.com/2076-3921/11/6/1078mitochondrial fusionblood flowshear stressarteriesendothelial cellatherosclerosis |
| spellingShingle | Ahmad Chehaitly Anne-Laure Guihot Coralyne Proux Linda Grimaud Jade Aurrière Benoit Legouriellec Jordan Rivron Emilie Vessieres Clément Tétaud Antonio Zorzano Vincent Procaccio Françoise Joubaud Pascal Reynier Guy Lenaers Laurent Loufrani Daniel Henrion Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis Antioxidants mitochondrial fusion blood flow shear stress arteries endothelial cell atherosclerosis |
| title | Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis |
| title_full | Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis |
| title_fullStr | Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis |
| title_full_unstemmed | Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis |
| title_short | Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis |
| title_sort | altered mitochondrial opa1 related fusion in mouse promotes endothelial cell dysfunction and atherosclerosis |
| topic | mitochondrial fusion blood flow shear stress arteries endothelial cell atherosclerosis |
| url | https://www.mdpi.com/2076-3921/11/6/1078 |
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