SUMMARY
Vascular beds show different propensities for different vascular pathologies, yet mechanisms explaining these fundamental differences remain unknown. We sought to build a transcriptomic, cellular, and spatial atlas of human arterial cells across multiple different arterial segments to understand this phenomenon. We found significant cell type-specific segmental heterogeneity. Determinants of arterial identity are predominantly encoded in fibroblasts and smooth muscle cells, and their differentially expressed genes are particularly enriched for vascular disease-associated loci and genes. Adventitial fibroblast-specific heterogeneity in gene expression coincides with numerous vascular disease risk genes, suggesting a previously unrecognized role for this cell type in disease risk. Adult arterial cells from different segments cluster not by anatomical proximity but by embryonic origin, with differentially regulated genes heavily influenced by developmental master regulators. Non-coding transcriptomes across arterial cells contain extensive variation in lnc-RNAs expressed in cell type- and segment-specific patterns, rivaling heterogeneity in protein coding transcriptomes, and show enrichment for non-coding genetic signals for vascular diseases.
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