Positional transcriptomics shed light on site-specific pathologies of the aorta

Abstract Pathologies of large vessels, such as atherosclerosis and aneurysms tend to emerge at specific sites. The consistency in their distribution suggests that a combination of unique local stressors, including both physical forces and specific gene expression profiles are confounding factors in disease etiology. Here we used single-cell RNA sequencing to identify signatures in smooth muscle cells with site-restricted predominance to uncover potentially relevant gene products. We showed that a small cohort of transcripts (5.5%) display preferential expression at specific sites of the vascular tree and in accordance with their embryological origin. Importantly, in silico studies revealed that several of these genes mapped to linkage studies for which no specific disease-causing candidates had been previously found. One of these candidates was Mcam/CD146 that mapped to the familial aortic aneurysm 1 (FAA1) locus identified by linkage analysis two decades ago. We showed that Mcam was significantly reduced in the AngII / hypercholesterolemic model of aortic aneurysm and further demonstrated that absence of the gene in mice resulted in larger lesions and accelerated death due to dissection. Our study highlighted site-specific alterations in gene expression profiles of smooth muscle cells that yield important insight in understanding site-specific vascular pathologies.