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Primary adventitial fibroblast response to TGFb is dependent on vascular site and implicates functional developmental epigenomic memory

ABSTRACT: We have shown that vascular SMCs, fibroblasts, and endothelial cells have transcriptional and epigenomic features that are distinct to vascular site. Further, TF motif accessibility analysis in fibroblasts reveals an increased accessibility of AP1, and SMAD2:3:4, and TCF21 motifs in the ascending fibroblast population compared to carotid and descending fibroblasts, with further gene regulatory network analysis suggesting distinct regulatory TF module activity in ascending fibroblasts highlighting master regulator of fibroblast activation Meox1. This differential chromatin accessibility would suggest the potential for heightened biological response to TGFb in ascending fibroblasts. To evaluate the functional effect of this differential chromatin accessibility and to identify if differential gene expression is retained following removal from vascular site flow conditions, we isolated and cultured primary adventitial fibroblasts from healthy 14 week old C57BL/6 mice from the ascending and descending aorta and stimulated them with control or TGFb (10ng/mL, 48hrs) and performed bulk RNA sequencing (n = 3 per condition).

ORGANISM(S): Mus musculus

PROVIDER: GSE296074 | GEO | 2025/07/29

REPOSITORIES: GEO

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Project description:Vascular sites have distinct susceptibility to atherosclerosis and aneurysm, yet the biological underpinning of vascular site-specific disease risk is largely unknown. Vascular tissues have different developmental origins that may influence global chromatin accessibility, and understanding differential chromatin accessibility, gene expression profiles, and gene regulatory networks (GRN) on single cell resolution may give key insight into vascular site-specific disease risk. Here, we performed single cell chromatin accessibility (scATACseq) and gene expression profiling (scRNAseq) of healthy adult mouse vascular tissue from three vascular sites, 1) aortic root and ascending aorta, 2) brachiocephalic and carotid artery, and 3) descending thoracic aorta. Through a comprehensive analysis at single cell resolution, we discovered key regulatory enhancers to not only be cell type, but vascular site specific in vascular smooth muscle (SMC), fibroblasts, and endothelial cells. 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 and discovered transcription factor motif accessibility to be cell type and vascular site specific. Notably, we identify ascending fibroblasts to have distinct epigenomic patterns, highlighting SMAD2/3 function to suggest a differential susceptibility to TGF, a finding we confirmed through in vitro culture of primary adventitial fibroblasts. Finally, to understand how vascular site-specific enhancers may regulate human genetic risk to disease, we integrated genome wide association study (GWAS) data for ascending and descending aortic dimension, and through using a novel technique, we employed ChromBPNet, a distinct base resolution deep learning model to predict variant effect on chromatin accessibility We trained nine ChromBPNet models to predict variant effect in SMC, Fibroblasts, and Endothelial cells within ascending aorta, carotid, and descending aorta sites of origin. We reveal that although cell type remains a primary influence on variant effect, vascular site modifies effect within cell type and highlights genomic regions that are enriched for specific TF motif footprints — including MEF2A, SMAD3, and HAND2. This work supports a paradigm that the epigenomic and transcriptional landscapes of vascular cells are cell type and vascular site-specific and that these vascular site-specific enhancers govern complex genetic drivers of vascular site-specific disease risk.

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Primary adventitial fibroblast response to TGFb is dependent on vascular site and implicates functional developmental epigenomic memory

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