Alternative Splicing of FN (Fibronectin) Regulates the Composition of the Arterial Wall Under Low Flow
Name
Murphy et al ATVB prepub final.pdf
Description
Accepted version
Size
11.75 MB
Format
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Checksum (MD5)
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Author(s)
Murphy, Patrick Andries
Jailkhani, Noor
Nicholas, Sarah-Anne
Del Rosario, Amanda M
Balsbaugh, Jeremy L.
Begum, Shahinoor
Kimble, Amy
Hynes, Richard O
Date Issued
November 2020
Journal
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Citation
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
Version
Author's final manuscript
Abstract
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1161/atvbaha.120.314013
