Abstract
Abstract only Aims: Arteries and veins respond differently to injury, with significantly higher rates of postsurgical failure in the latter. The biological reasons for this discrepancy are not well understood, which is a limiting factor for the development of vein-targeted therapies. This study contrasts peripheral arteries and veins at the single-cell level, with a focus on cell populations with remodeling potential. Methods and Results: Upper arm arteries (brachial) and veins (basilic/cephalic) from 27 organ donors were compared using a combination of bulk and single-cell RNA sequencing, proteomics, flow cytometry, and histology. The cellular atlases of six arteries and veins demonstrated a significantly higher proportion of smooth muscle cells (SMCs) in arteries vs. higher counts of fibroblasts in veins. In both types of vessels, clustering analyses identified an intermediate myofibroblast population with repair characteristics. Both arterial and venous myofibroblasts were characterized by upregulation of F2R , FN1, POSTN, COL8A1, and ITGA10 , and were confirmed by histology and F2R/CD90 double staining by flow cytometry. However, bioinformatic analyses indicate that arterial myofibroblasts are phenotypically related to both SMCs and fibroblasts, whereas in veins they are predominantly fibroblast derived. Differences in wall structure further explain the distinct contributions of SMC and fibroblasts to these reparative populations. PDGFRA + fibroblasts are almost exclusively located outside the external elastic lamina in arteries, while widely distributed throughout the venous wall. In line with a higher abundance of fibroblasts and fibroblast-derived reparative cells, ECM-targeted proteomics confirmed a higher abundance of fibrillar collagens in veins vs. more basement ECM components in arteries. These differences in ECM composition are also associated with vessel-specific modulation of myofibroblast differentiation. Conclusions: The distinct cellular origins and transcriptional programs of myofibroblast populations in arteries and veins may explain differences in acute and chronic wall remodeling between vessels. This information is relevant for the development of anti-stenotic therapies.