Background <p>Atherosclerosis and aortic aneurysms are prevalent aortic disorders. Significantly, atherosclerosis frequently impacts the common carotid artery (CA), whereas aortic aneurysms typically involve the abdominal aorta (AA), indicating possible heterogeneity between CA and AA with an ambiguous underlying mechanism. Sphingolipids, a crucial branch of lipid metabolism, has increasingly garnered attention in vascular diseases by influencing the phenotypic regulation of vascular smooth muscle cells (VSMCs). Nevertheless, whether sphingolipids play a role in the heterogeneity between CA and AA and in disease susceptibility remains uncertain.</p> Methods and results <p>Public transcriptomics were employed to clarify the distinctions in contractility and calcification of VSMCs in relation to the vulnerability of human AA and CA to aortic aneurysms and atherosclerosis, respectively. Bulk RNA-seq revealed transcriptomic variances in the biology of VSMCs between AA and CA from rats. Primary VSMCs from AA (AASMC) and CA (CASMC) were isolated for further validation. The specific variations in sphingolipid metabolism (comprising 8 classes of sphingolipids with 169 species) between AA and CA from rats were further characterized using UPLC–QTOF-MS-based lipidomics. Most sphingolipids, except sphingomyelin, were significantly elevated in CA compared to AA. Ceramides were the major contributor to these differences, which was further confirmed by in situ immunofluorescence of AA and CA from rats and healthy humans. The differential expression of genes involved in ceramide biosynthesis (<i>Cers1-4</i>), transport (<i>Cert1</i>), and metabolic processes (<i>Smpd1</i>, <i>Sgpp1</i>, <i>Sphk2</i>, and <i>Sgms1/2</i>), along with variations in subcellular organelles in VSMCs, contributed to the heterogeneity of sphingolipid metabolism between AA and CA. The effects of ceramides on VSMC biology were subsequently assessed using primary VSMCs. Specifically, AASMC exhibited greater contractility and lower susceptibility to calcification compared to CASMC. Exogenous ceramides heightened the susceptibility to calcification in both CASMC and AASMC, whereas the inhibition of ceramide synthases engendered an opposing consequence. Notably, in CA from patients with atherosclerosis but not AA from aortic aneurysms, the activation of sphingolipid metabolism (including ceramides) was positively correlated with calcification and negatively correlated with the regulatory processes of VSMC contraction. Furthermore, the ceramide metabolism was activated along with calcification in CA, which corresponded with the accumulation of ceramide in atherosclerotic plaques of human.</p> Conclusions <p>In this study, we identified ceramides, a major class of sphingolipid metabolites, as a promising determinant in unequal biology and susceptibility to calcification of CA and AA. Our results reveal the previously unappreciated role of sphingolipid metabolism, particularly ceramides, in regional vascular pathology. These findings provide novel insights that inform our understanding of disease mechanisms and highlight potential ways for future therapeutic exploration.</p> Graphical Abstract <p>Sphingolipids' role in vascular heterogeneity between common carotid artery (CA) and abdominal aorta (AA) have been elucidated through a comprehensive approach involving public transcriptomics, RNA sequencing, and lipidomics. Ceramides, key in sphingolipid metabolism, modulate contractility and calcification differences in vascular smooth muscle cells (VSMCs) between CA and AA. </p>