The role of the atypical cadherin Fat1 in the regulation of vascular smooth muscle cells during atherosclerosis
Dunaway AItamirano, Charlene Marie
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Fat1 is an atypical cadherin that controls vascular smooth muscle cell (SMC) growth and migration. After arterial injury, SMC-specific Fat1-knockout (fat1SMKO) mice exhibit exacerbated neointima formation with increased SMC proliferation and decreased SMC marker gene expression. In recent studies, we found that Fat1 expression colocalizes with SMCs in atherosclerotic lesions from apolipoprotein E-/- (Apoe-/-) mice. We hypothesize that Fat1 regulation of SMC activities is important in limiting atherogenesis. To test this, we generated fat1SMKO; Apoe-/- double-knockout (DKO) mice and assessed atherosclerosis after 24 weeks on a high fat diet, analyzing aortic roots and brachiocephalic arteries (BCA) for lesion area and immunohistochemical features. DKO mice (N=10) exhibited larger lesions with thicker fibrous caps and larger necrotic cores. Furthermore, DKO lesions displayed increased proliferation and SMC content. The intermediate filament protein vimentin was recently identified as a novel Fat1 interactor. Fat1 and vimentin expression colocalized within the fibrous cap area of atherosclerotic lesions. Moreover, Fat1-deficient SMCs and lesions exhibited increased vimentin levels, and knockdown studies suggest that vimentin plays a role in SMC growth. SMC Fat1 deficiency also resulted in increased beta-catenin levels and upregulation of beta-catenin target genes, Axin2 and Snail1. Concomitantly, SMC Fat1 deficiency caused reduced E-cadherin expression and promoter activity. In summary, Fat1-deficient SMCs undergo changes in expression of genes associated with epithelial-to-mesenchymal transition in proper epithelial cells. These findings suggest that components of this regulatory network are operative in SMCs, and controlled by Fat1, which promotes a state of quiescence in SMCs that opposes atherosclerotic lesion expansion.
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