Exploring Origin-dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases via Intersectional Genetics

The developmental heterogeneity of smooth muscle cells (SMCs) plays a crucial role in the prevalence of segment-specific aortic diseases. Traditional genetic tools, however, are insufficient for in vivo analysis of disease susceptibility associated with cellular origin. To overcome this challenge, we engineered a state-of-the-art dual recombinase-mediated intersectional genetic system, tailored to precisely target SMCs from distinct developmental origins. Employing this system, we selectively knocked out Tgfbr2 in the ascending aorta and Smad4 in the aortic arch. Our results distinctly demonstrate the indispensable roles these genes play in sustaining SMC integrity across different aortic segments. This advanced genetic system not only deepens our understanding of aortopathies but also significantly enhances the potential for modeling and elucidating the mechanisms driving segment-specific aortic diseases. Aortic cells were harvested from adult mice each of CNC-SMC-Cre;R26-tdT and CNC-SMC-Cre;Smad4flox/flox;R26-tdT genotyped and analyzed using scRNA-seq.