Integrated chromatin accessibility and transcriptomic profiling provide insights into inflammation-associated endothelial remodeling in capillary malformations

Capillary malformation (CM) is a congenital vascular anomaly yet the regulatory mechanisms driving endothelial remodeling remain incompletely defined. Our previous data have shown that CM lesion-derived induced pluripotent stem cells (iPSCs), their induced ECs (iECs) and vascular organoids preserve vascular phenotypes. These models do not harbor detectable GNAQ p.R183Q and other common low varaint allele frequency mutations after reprogramming. To further explore the pathological signaling underlying endothelial phenotypes in these models, we profiled bulk chromatin accessibility from ATAC-seq and gene expression from RNA-seq in CM and control iECs. A panel of integrated genes was revealed by intersecting differentially accessible regions, differentially expressed genes, and peak-to-gene candidate links. The signatures of this panel highlighted the enriched pathways involving stem cell development and differentiation, inflammatory signaling, extracellular matrix reorganization, and endothelial function. Locus-level of KLF6 and TGF-beta-induced loci illustrated concordant accessibility and expression changes in CM iECs. These results are consistent with a model of inflammation-associated endothelial remodeling in CM. Furthermore, several transcription factors and transcriptional co-regulators associated with endothelial differentiation displayed increased distal chromatin accessibility accompanied by reduced transcript abundance. This data suggests that distal regulatory elements may participate in active transcriptional repression and contribute to impaired endothelial differentiation in CM iECs.