Transcription factors regulating vasculogenesis and angiogenesis

Abstract

Transcription factors (TFs) play a crucial role in regulating the dynamic and precise patterns of gene expression required for the initial specification of endothelial cells (ECs), and during endothelial growth and differentiation. While sharing many core features, ECs can be highly heterogeneous. Differential gene expression between ECs is essential to pattern the hierarchical vascular network into arteries, veins and capillaries, to drive angiogenic growth of new vessels, and to direct specialization in response to local signals. Unlike many other cell types, ECs have no single master regulator, instead relying on differing combinations of a necessarily limited repertoire of TFs to achieve tight spatial and temporal activation and repression of gene expression. Here, we will discuss the cohort of TFs known to be involved in directing gene expression during different stages of mammalian vasculogenesis and angiogenesis, with a primary focus on development.

A catalogue of verified and characterized arterial enhancers for key arterial identity genes

“…In silico identification of putative enhancers for key arterial identity genes Transcription factors primarily regulate endothelial gene transcription through binding to enhancers (cis-regulatory elements) 1 . Consequently, analysis of enhancer sequences can elucidate the precise combination of transcription factors, and cognate upstream signalling pathways, involved in different patterns of gene expression.…”

“…To identify putative enhancers in silico, we used five published datasets detailing different enhancer-associated chromatin marks: (i) open chromatin as assessed by ATAC-seq in primary mouse adult aortic ECs (MAECs) from Engelbrecht et al 55 ; (ii) open chromatin as assessed by ATAC-seq in mouse postnatal day 6 (P6) retina ECs (MRECs) from Yanagida et al 56 ; (iii) enriched EP300 binding in Tie2Cre+ve cells from embryonic day (E)11.5 mouse embryos (from Zhou et al 53 ); (iv) enriched H3K27Ac and/or H3K4Me1 in human umbilical vein ECs (HUVECs, data available on the UCSC genome browser 57 ); and (v) open chromatin regions assessed by DNAseI hypersensitivity in HUVECs and dermal-derived neonatal and adult blood microvascular ECs (HMVEC-dBl-neo/ad) comparative to non-ECs (UCSC genome browser 57 ). A retrospective analysis of 32 previously described mammalian in vivo -validated EC enhancers 1 , which included eight arterial enhancers, found that 31/32 were marked by at least one enhancer mark in both human and mouse samples (including 8/8 of arterial enhancers), see Table S1. We next analysed the loci of our target arterial genes to identify putative enhancers using these enhancer marks (Figure S1).…”

“…Table 1 Summary of putative enhancer activity in mosaic Tol2 transgenic zebrafish. "In vivo classification" indicates the results of this screen, "in vitro classification" indicates previous designation in 32 , as defined by relative enhancer and promoter marks in HUVECs vs HUAECs.…”

“…The blood vessel system consists of a highly branched network of tubes lined by endothelial cells (ECs) and hierarchically organised into arteries, veins, and capillaries. The EC layer is the first part of the blood vessel to form, initially via differentiation from mesoderm (vasculogenesis) and later from existing ECs (angiogenesis) 1 . While the first arterial ECs arise during vasculogenesis 2 , single cell transcriptomics and fate mapping experiments spanning humans, mice and zebrafish indicate that most arterial ECs form via angiogenesis from venous and venous-like capillary ECs [3][4][5][6][7][8][9][10][11] .…”

From pumps to pipes: A special issue on mechanisms of cardiovascular development

“…In particular, the mechanisms that control myofibril maturation, the metabolic processes underlying maturation and polyploidization of cardiomyocytes are extensively reviewed, and how these processes are altered in regeneration outlined in detail. Payne et al, 2 then provide a detailed overview of the transcription factors that control developmental angiogenesis and vasculogenesis. This helpful resource, points readers to detailed information on binding motifs, phenotypes in mice and zebrafish, and gaps in the current understanding of transcriptional control of vascular development.…”