Abstract Rationale Vascular beds have distinct susceptibility to atherosclerosis and aneurysm, yet the biological underpinnings of vascular bed specific disease risk are largely unknown. Vascular tissues have different developmental origins which may influence global chromatin accessibility. Understanding chromatin accessibility and gene expression profiles on single cell resolution is crucial to gain insight into vascular bed specific disease risk. Objective We aim to understand, at single cell resolution, the global chromatin accessibility and gene expression profiles across distinct vascular beds in the healthy adult mouse to provide insight into the potential mechanisms of vascular bed specific disease risk. Methods and Results We performed single cell chromatin accessibility (scATACseq) and gene expression profiling (scRNAseq) of healthy adult mouse vascular tissue from three vascular beds, 1) aortic root and ascending aorta, 2) brachiocephalic and carotid artery, and 3) descending thoracic aorta. By integrating datasets and comparing vascular beds within cell type, we identified thousands of differentially accessible chromatin peaks within smooth muscle cells, fibroblasts, and endothelial cells, demonstrating numerous enhancers to be vascular bed specific. We revealed an epigenetic ‘memory’ of embryonic origin with differential chromatin accessibility of key developmental transcription factors such as Tbx20 , Hand2 , Gata4 , and Hoxb family members. Increased transcription factor motif accessibility in ascending fibroblasts compared to descending further highlights SMAD2/3 functions and suggests a differential susceptibility to TGFβ. By isolating primary adventitial fibroblasts from ascending and descending thoracic aorta from adult mice, we demonstrate ascending fibroblasts to have a distinctly higher transcriptional response to TGFβ compared to descending fibroblasts, highlighting that distinct chromatin accessibility between vascular beds is retained following primary in vitro culture and influences responsiveness to disease relevant signaling. Conclusions This work supports a paradigm that the epigenomic and transcriptional landscapes of vascular cells are cell type and vascular bed specific and that differentially accessible regions are enriched for disease risk genes.

The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci