Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow
Objective: Exposure of the arterial endothelium to low and disturbed flow is a risk factor for the erosion and rupture of atherosclerotic plaques and aneurysms. Circulating and locally produced proteins are known to contribute to an altered composition of the extracellular matrix at the site of lesi...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Ovid Technologies (Wolters Kluwer Health)
2021
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| Online Access: | https://hdl.handle.net/1721.1/131166 |
| _version_ | 1811082827653971968 |
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| author | Murphy, Patrick Andries Jailkhani, Noor Nicholas, Sarah-Anne Del Rosario, Amanda M Balsbaugh, Jeremy L. Begum, Shahinoor Kimble, Amy Hynes, Richard O |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Murphy, Patrick Andries Jailkhani, Noor Nicholas, Sarah-Anne Del Rosario, Amanda M Balsbaugh, Jeremy L. Begum, Shahinoor Kimble, Amy Hynes, Richard O |
| author_sort | Murphy, Patrick Andries |
| collection | MIT |
| description | Objective: Exposure of the arterial endothelium to low and disturbed flow is a risk factor for the erosion and rupture of atherosclerotic plaques and aneurysms. Circulating and locally produced proteins are known to contribute to an altered composition of the extracellular matrix at the site of lesions, and to contribute to inflammatory processes within the lesions. We have previously shown that alternative splicing of FN (fibronectin) protects against flow-induced hemorrhage. However, the impact of alternative splicing of FN on extracellular matrix composition remains unknown. Approach and Results: Here, we perform quantitative proteomic analysis of the matrisome of murine carotid arteries in mice deficient in the production of FN splice isoforms containing alternative exons EIIIA and EIIIB (FN-EIIIAB null) after exposure to low and disturbed flow in vivo. We also examine serum-derived and endothelial-cell contributions to the matrisome in a simplified in vitro system. We found flow-induced differences in the carotid artery matrisome that were impaired in FN-EIIIAB null mice. One of the most interesting differences was reduced recruitment of FBLN1 (fibulin-1), abundant in blood and not locally produced in the intima. This defect was validated in our in vitro assay, where FBLN1 recruitment from serum was impaired by the absence of these alternatively spliced segments. Conclusions: Our results reveal the extent of the dynamic alterations in the matrisome in the acute response to low and disturbed flow and show how changes in the splicing of FN, a common response in vascular inflammation and remodeling, can affect matrix composition. |
| first_indexed | 2024-09-23T12:09:46Z |
| format | Article |
| id | mit-1721.1/131166 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:09:46Z |
| publishDate | 2021 |
| publisher | Ovid Technologies (Wolters Kluwer Health) |
| record_format | dspace |
| spelling | mit-1721.1/1311662022-10-01T08:35:53Z Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow Murphy, Patrick Andries Jailkhani, Noor Nicholas, Sarah-Anne Del Rosario, Amanda M Balsbaugh, Jeremy L. Begum, Shahinoor Kimble, Amy Hynes, Richard O Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Biology Objective: Exposure of the arterial endothelium to low and disturbed flow is a risk factor for the erosion and rupture of atherosclerotic plaques and aneurysms. Circulating and locally produced proteins are known to contribute to an altered composition of the extracellular matrix at the site of lesions, and to contribute to inflammatory processes within the lesions. We have previously shown that alternative splicing of FN (fibronectin) protects against flow-induced hemorrhage. However, the impact of alternative splicing of FN on extracellular matrix composition remains unknown. Approach and Results: Here, we perform quantitative proteomic analysis of the matrisome of murine carotid arteries in mice deficient in the production of FN splice isoforms containing alternative exons EIIIA and EIIIB (FN-EIIIAB null) after exposure to low and disturbed flow in vivo. We also examine serum-derived and endothelial-cell contributions to the matrisome in a simplified in vitro system. We found flow-induced differences in the carotid artery matrisome that were impaired in FN-EIIIAB null mice. One of the most interesting differences was reduced recruitment of FBLN1 (fibulin-1), abundant in blood and not locally produced in the intima. This defect was validated in our in vitro assay, where FBLN1 recruitment from serum was impaired by the absence of these alternatively spliced segments. Conclusions: Our results reveal the extent of the dynamic alterations in the matrisome in the acute response to low and disturbed flow and show how changes in the splicing of FN, a common response in vascular inflammation and remodeling, can affect matrix composition. NIH NHLBI (Grant K99/R00-HL125727) 2021-08-10T20:43:54Z 2021-08-10T20:43:54Z 2020-11 2020-01 2021-08-06T17:29:17Z Article http://purl.org/eprint/type/JournalArticle 1079-5642 1524-4636 https://hdl.handle.net/1721.1/131166 Murphy, Patrick A. et al. "Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow." Arteriosclerosis, Thrombosis, and Vascular Biology 41, 1 (November 2020): e18–e32. © 2020 Lippincott Williams and Wilkins en http://dx.doi.org/10.1161/atvbaha.120.314013 Arteriosclerosis, Thrombosis, and Vascular Biology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Ovid Technologies (Wolters Kluwer Health) Prof. Richard Hynes |
| spellingShingle | Murphy, Patrick Andries Jailkhani, Noor Nicholas, Sarah-Anne Del Rosario, Amanda M Balsbaugh, Jeremy L. Begum, Shahinoor Kimble, Amy Hynes, Richard O Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow |
| title | Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow |
| title_full | Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow |
| title_fullStr | Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow |
| title_full_unstemmed | Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow |
| title_short | Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow |
| title_sort | alternative splicing of fn fibronectin regulates the composition of the arterial wall under low flow |
| url | https://hdl.handle.net/1721.1/131166 |
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