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Vascular endothelial cells (EC) display remarkable plasticity during development, acquiring organ-specific molecular and cellular specializations. In this thesis, we explore the genomic basis of this heterogeneity by analyzing and comparing the transcriptome, accessible chromatin, and DNA methylome landscapes from mouse brain, liver, lung, and kidney ECs. Analysis of transcription factor (TF) gene expression and TF DNA binding motifs at candidate cis-regulatory elements (CREs) reveals both shared and organ-specific EC regulatory networks. Putative CREs for brain ECs exhibit enrichment of DNA binding motifs of the TCF/LEF family of TFs, the effectors of canonical Wnt/beta-catenin signaling in the nucleus. In acutely cultured brain ECs, the rapid loss of blood-brain barrier (BBB) markers is closely correlated with down-regulation of canonical Wnt/beta-catenin signaling. In the early postnatal brain, single-cell RNA-seq of purified ECs reveals (1) close relationships between veins and mitotic cells and between arteries and tip cells,(2) a division of capillary ECs into vein-like and artery-like classes, and (3) new endothelial subtype markers, including new validated tip cell markers. As part of this thesis, we have also demonstrated that induction of canonical Wnt/beta-catenin signaling promotes a BBB transcriptional and chromatin state in the normally high-permeability ECs of the pituitary gland and choroid plexus. Lastly, we identify a role for ZIC3 in central nervous system (CNS) vascular EC fitness. This observation implies the presence of a strong feedback control system during CNS vascular development and of an ongoing quality control …