Abstract
Thoracic aortic aneurysm and dissection (TAAD) involves a progressive dilation of the aortic wall associated with degradation of the extracellular matrix (ECM), cystic medial degeneration, smooth muscle cell (SMC) dysfunction, and rarefaction. TAAD etiology and pathogenesis suggest that alteration of mechanical force propagation may contribute to SMC dysfunction. This study aims to determine the role of SMC focal adhesion proteins, which are key components of force transmission, in TAAD pathogenesis. scRNA-seq analysis of human TAA aortas showed reduced expression of intracellular focal adhesion components, including PTK2 (FAK), VCL, ILK, and TES transcripts, in SMCs. Additionally, protein levels of FAK, ILK, and VCL were decreased in the aorta of patients with TAA. SMC-specific Ptk2, Vcl, and Ilk KO mice treated with β-aminopropionitrile (BAPN) exhibited increased mortality, aortic dilation, ECM breakdown, and SMC loss. Mechanistically, knocking down FAK, ILK, and VCL exacerbated gliotoxin-induced SMC anoikis, whereas overexpressing full-length WT and dead-kinase FAK conferred resistance to apoptosis and cell detachment, indicating that FAK’s protective effects depend on its expression rather than its enzymatic activity. Inhibition of FAK kinase activity did not affect SMC apoptosis in vitro or aortic dilation in vivo. Our findings demonstrate that the expression of focal adhesion proteins protects against TAAD progression and SMC anoikis independently of FAK kinase activity.
Authors
Zhenyuan Zhu, Mingjun Liu, Jianxin Wei, Deepa Suryanarayan, Parya Behzadi, Robert Edgar, Julie A. Phillippi, Cynthia St. Hilaire, Cristina Espinosa-Diez, Delphine Gomez
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