Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome
Background. The leading cause of mortality in patients with Marfan syndrome (MFS) is thoracic aortic aneurysm and dissection. Notch signaling is essential for vessel morphogenesis and function. However, the role of Notch signaling in aortic pathology and aortic smooth muscle cell (SMC) differentiati...
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2022/7538649 |
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| author | Kathryn Jespersen Chenxin Li Rishi Batra Christopher A. Stephenson Paul Harding Kylie Sestak Ryan T. Foley Harrison Greene Trevor Meisinger Jason R. Cook B. Timothy Baxter Wanfen Xiong |
| author_facet | Kathryn Jespersen Chenxin Li Rishi Batra Christopher A. Stephenson Paul Harding Kylie Sestak Ryan T. Foley Harrison Greene Trevor Meisinger Jason R. Cook B. Timothy Baxter Wanfen Xiong |
| author_sort | Kathryn Jespersen |
| collection | DOAJ |
| description | Background. The leading cause of mortality in patients with Marfan syndrome (MFS) is thoracic aortic aneurysm and dissection. Notch signaling is essential for vessel morphogenesis and function. However, the role of Notch signaling in aortic pathology and aortic smooth muscle cell (SMC) differentiation in Marfan syndrome (MFS) is not completely understood. Methods. RNA-sequencing on ascending aortic tissue from a mouse model of MFS, Fbn1mgR/mgR, and wild-type controls was performed. Notch 3 expression and activation in aortic tissue were confirmed with real-time RT-PCR, immunohistochemistry, and Western blot. Fbn1mgR/mgR and wild-type mice were treated with a γ-secretase inhibitor, DAPT, to block Notch activation. Aortic aneurysms and rupture were evaluated with connective tissue staining, ultrasound, and life table analysis. Results. The murine RNA-sequencing data were validated with mouse and human MFS aortic tissue, demonstrating elevated Notch3 activation in MFS. Data further revealed that upregulation and activation of Notch3 were concomitant with increased expression of SMC contractile markers. Inhibiting Notch3 activation with DAPT attenuated aortic enlargement and improved survival of Fbn1mgR/mgR mice. DAPT treatment reduced elastin fiber fragmentation in the aorta and reversed the differentiation of SMCs. Conclusions. Our data demonstrated that matrix abnormalities in the aorta of MFS are associated with increased Notch3 activation. Enhanced Notch3 activation in MFS contributed to aortic aneurysm formation in MFS. This might be mediated by inducing a contractile phenotypic change of SMC. Our results suggest that inhibiting Notch3 activation may provide a strategy to prevent and treat aortic aneurysms in MFS. |
| format | Article |
| id | doaj-art-35b0749cb78247e98cfac514fcd25903 |
| institution | Kabale University |
| issn | 2314-7156 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-35b0749cb78247e98cfac514fcd259032025-02-03T00:59:32ZengWileyJournal of Immunology Research2314-71562022-01-01202210.1155/2022/7538649Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan SyndromeKathryn Jespersen0Chenxin Li1Rishi Batra2Christopher A. Stephenson3Paul Harding4Kylie Sestak5Ryan T. Foley6Harrison Greene7Trevor Meisinger8Jason R. Cook9B. Timothy Baxter10Wanfen Xiong11Department of SurgeryDepartment of OphthalmologyDepartment of SurgeryDepartment of SurgeryDepartment of SurgeryDepartment of SurgeryDepartment of SurgeryDepartment of SurgeryDepartment of SurgeryDepartment of SurgeryDepartment of SurgeryDepartment of SurgeryBackground. The leading cause of mortality in patients with Marfan syndrome (MFS) is thoracic aortic aneurysm and dissection. Notch signaling is essential for vessel morphogenesis and function. However, the role of Notch signaling in aortic pathology and aortic smooth muscle cell (SMC) differentiation in Marfan syndrome (MFS) is not completely understood. Methods. RNA-sequencing on ascending aortic tissue from a mouse model of MFS, Fbn1mgR/mgR, and wild-type controls was performed. Notch 3 expression and activation in aortic tissue were confirmed with real-time RT-PCR, immunohistochemistry, and Western blot. Fbn1mgR/mgR and wild-type mice were treated with a γ-secretase inhibitor, DAPT, to block Notch activation. Aortic aneurysms and rupture were evaluated with connective tissue staining, ultrasound, and life table analysis. Results. The murine RNA-sequencing data were validated with mouse and human MFS aortic tissue, demonstrating elevated Notch3 activation in MFS. Data further revealed that upregulation and activation of Notch3 were concomitant with increased expression of SMC contractile markers. Inhibiting Notch3 activation with DAPT attenuated aortic enlargement and improved survival of Fbn1mgR/mgR mice. DAPT treatment reduced elastin fiber fragmentation in the aorta and reversed the differentiation of SMCs. Conclusions. Our data demonstrated that matrix abnormalities in the aorta of MFS are associated with increased Notch3 activation. Enhanced Notch3 activation in MFS contributed to aortic aneurysm formation in MFS. This might be mediated by inducing a contractile phenotypic change of SMC. Our results suggest that inhibiting Notch3 activation may provide a strategy to prevent and treat aortic aneurysms in MFS.http://dx.doi.org/10.1155/2022/7538649 |
| spellingShingle | Kathryn Jespersen Chenxin Li Rishi Batra Christopher A. Stephenson Paul Harding Kylie Sestak Ryan T. Foley Harrison Greene Trevor Meisinger Jason R. Cook B. Timothy Baxter Wanfen Xiong Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome Journal of Immunology Research |
| title | Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome |
| title_full | Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome |
| title_fullStr | Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome |
| title_full_unstemmed | Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome |
| title_short | Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome |
| title_sort | impact of notch3 activation on aortic aneurysm development in marfan syndrome |
| url | http://dx.doi.org/10.1155/2022/7538649 |
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