Abstract 11068: Smad3-Deficiency in Murine Smooth Muscle Cells Causes Global Defects in Expression of Focal Adhesion Components, but Drives Subset-Specific Compensatory Mechanisms Promoting Matrix Degradation and Oxidative Stress

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The pathogenesis of aortic aneurysms caused by mutations that impair TGF-β/Smad signaling without completely ablating it remains unclear. To investigate TGF-β’s role independently of its developmental functions, we used mouse models to inactivate Smad3 specifically in smooth muscle cells (SMCs) at 6 weeks of age, when postnatal matrix deposition is largely completed. This intervention was sufficient to induce dilation in the aortic root, but not the ascending aorta. To identify factors underlying this regional vulnerability, we analyzed aortas from control and Smad3-deficient mice by single-cell transcriptomics 10 weeks and 18 weeks after deletion, when dilation is undetectable and moderate, respectively. Three major SMC clusters were identified regardless of genotype or time-point. In situ hybridization showed that the aortic root and proximal ascending aorta were enriched in SMCs expressing cluster-defining transcripts for Cluster 3 and 2, while distal ascending and aortic arch were for Cluster 1. At the early time-point, all SMC clusters showed defective expression of genes coding for components ( Fblim1 , Svil , Tes and Tln1 ) and regulators ( Abra and Rock1) of focal adhesions in response to Smad3 inactivation. These defects associated with Cluster 3-specific upregulation of positive effectors of the TGF-β pathway, such as Tgfb2, and down-regulation of negative regulators of Angiotensin II signaling, such as Rgs2 and Rgs4 . At the later time point, whereas Smad3-deficient SMCs in Cluster 3 retained a similar profile, those in Cluster 2 showed transcriptional alterations consistent with increased TGF-β/Smad2 activation, accompanied by upregulation of Neat1 , a lnc-RNA critical for SMC phenotypic switching. These included potentially adaptive changes, such as upregulation of genes coding for collagen and its processing enzymes ( Col1a2 , Col3a1, Lox and Loxl1), and maladaptive ones such as upregulation of proteases ( Fap and Mmp9) , and upregulation of enzymes promoting oxidative stress ( Nox4 ). These data suggest that Smad3-deficiency causes defective expression of focal adhesion machinery in SMCs, initiating secondary subset-specific compensatory mechanisms driving localized pathogenic increases in proteolysis and oxidative stress.

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