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Targeting Fibronectin-integrin α5 Signaling in Marfan Syndrome

May 12, 2023
by Kanika Jain

Fibronectin-integrin α5 signaling is a key driver of thoracic aortic aneurysms in Marfan syndrome, and targeting this pathway may be a potential therapeutic strategy.

A Yale-led study has discovered a new way to potentially treat aortic aneurysms (AA), a condition where the aorta ruptures, in individuals with Marfan Syndrome (MFS). Recently a study by Martin Schwartz, PhD, Robert W. Berliner Professor of Medicine, and professor of biomedical engineering and of cell biology, published in the journal Arteriosclerosis, Thrombosis and Vascular Biology, suggests that fibronectin amplifies inflammatory responses through its main receptor, integrin α5β1 in MFS.

MFS is a genetic disorder which affects the development of stable connective tissue, including the aorta. MFS is caused by mutations in the FBN1 gene that encode fibrillin-1. This leads to the destabilization of elastic fibers and accumulation of fibronectin (FN) in the extracellular matrix, which can contribute to the development of aortic aneurysms.

First authors Minghao Chen, PhD, and Cristina Cavinato, PhD, demonstrate that the increase in FN, resulting from fibrillin insufficiency, affects smooth muscle cells (SMCs). This occurs by decreasing contractile gene expression and activating inflammatory pathways (via integrin α5-NF-kB signaling), both of which contribute to aneurysm development. The authors used integrin α2 chimeric mice, crossed with Fbn1mgR/mgR (mgR: animal model of Marfan syndrome), to investigate the molecular mechanisms by which FN affects SMCs. They found that the mutation in integrin α5/2 greatly prolonged the survival of Marfan mice and improved the integrity of elastic fibers, mechanical properties, SMC density, and SMC contractile gene expression. The study highlights the NF-kB pathway as a critical regulator of the SMC phenotypic switching in the presence of FN. These findings suggest a potential therapeutic strategy for the treatment of MFS by targeting the adverse signaling pathways involving FN-integrin α5.

Other authors of this study are Jens Hansen, Ravi Iyengar, Keiichiro Tanaka, Pengwei Ren, Abdulrahman Hassab, David S. Li, Eric Youshao, George Tellides, and Jay D. Humphrey.

Submitted by Elisabeth Reitman on May 12, 2023