Fibronectin-integrin α5 signaling promotes thoracic aortic aneurysm in a mouse model of Marfan syndrome

chen, m.; Cavinato, C.; Hansen, J.; Tanaka, K.; ren, p.; Hassab, A.; li, d. s.; Joshuao, E.; Tellides, G.; Iyengar, R.; Humphrey, J. D.; Schwartz, M.

doi:10.1101/2022.08.16.504169

bioRxiv · 10.1101/2022.08.16.504169

Fibronectin-integrin α5 signaling promotes thoracic aortic aneurysm in a mouse model of Marfan syndrome

chen, m.·Cavinato, C.·Hansen, J.·Tanaka, K.·ren, p.·Hassab, A.·li, d. s.·Joshuao, E.·Tellides, G.·Iyengar, R.·Humphrey, J. D.·Schwartz, M.

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Abstract

BackgroundMarfan syndrome, caused by mutations in the gene for the extracellular matrix (ECM) glycoprotein fibrillin-1, leads to thoracic aortic aneurysms (TAAs). Phenotypic modulation of vascular smooth muscle cells (SMCs) and ECM remodeling are characteristics of both non-syndromic and Marfan aneurysms. The ECM protein fibronectin (FN) is elevated in the tunica media of TAAs and amplifies inflammatory signaling in endothelial and SMCs through its main receptor, integrin 5{beta}1. We investigated the role of integrin 5-specific signals in Marfan mice in which the cytoplasmic domain of integrin 5 was replaced with that of integrin 2 (denoted 5/2 chimera). MethodsWe used 5/2 chimera mouse crossed with Fbn1mgR/mgR genetic background (mgR, a mouse model of Marfan syndrome) to compare the survival rate and pathogenesis of TAAs among wild type, 5/2, mgR and 5/2; mgR mice. Further biochemical and microscopic analysis of porcine and mouse aortic SMCs allowed us to identify the molecular mechanisms by which FN affects SMCs and subsequent development of TAAs. ResultsFN was elevated in the thoracic aortas from Marfan patients, in non-syndromic aneurysms and in the mgR mouse model of Marfan syndrome. The 5/2 mutation greatly prolonged survival of Marfan mice, with improved elastic fiber integrity, mechanical properties, SMC density, and SMC contractile gene expression. Furthermore, in vitro, plating of wild-type, but not 5/2, SMCs on FN decreased contractile gene expression and activated inflammatory pathways. These effects correlated with increased NF-kB activation and immune cell infiltration in the mgR aortas, which was rescued in the 5/2 mgR aortas. ConclusionsFN-integrin 5 signaling is a significant driver of TAA in the mgR mouse model. This pathway warrants further investigation as a therapeutic target.

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chen, m., Cavinato, C., Hansen, J., Tanaka, K., ren, p., Hassab, A., li, d. s., Joshuao, E., Tellides, G., Iyengar, R., Humphrey, J. D., Schwartz, M.. 2022-08-16. Fibronectin-integrin α5 signaling promotes thoracic aortic aneurysm in a mouse model of Marfan syndrome. https://doi.org/10.1101/2022.08.16.504169

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