Transcriptional control of endothelial cell development

Abstract

The transcription factors that regulate endothelial cell development have been a focus of active research for several years, and many players in the endothelial transcriptional program have been identified. This review discusses the function of several major regulators of endothelial transcription, including members of the Sox, Ets, Forkhead, GATA, and Kruppel-like families. This review also highlights recent developments aimed at unraveling the combinatorial mechanisms and transcription factor interactions that regulate endothelial cell specification and differentiation during vasculogenesis and angiogenesis.

Figure 1

Schematic representation of endothelial development from mesodermal progenitors. Endothelial cells development in the extraembryonic mesoderm in the yolk sac within blood islands, which contain an inner layer of hematotoietic cells and outer layer of angioblasts. From these blood islands, a primitive vascular plexus is formed. Within the embryo itself, angioblasts arise from mesodermal progenitors to form the aortae, cardinal veins and the endocardium (not depicted). The primitive embryonic and extraembryonic vasculature is then extensively remodeled via angiogenic processes. Mature, differentiated arteries, veins and lymphatic vessels are formed from the remodeled embryonic vasculature.

Figure 2

Schematic depiction of the vascular and hematopoietic phenotypes in Tal1-null mouse embryos at E9.5. A representation of the yolk sac vasculature is shown. Compared to wild-type embryos (A, C), Tal1 mutant embryos show an absence of blood cells (white circles). Remodeling of the vascular endothelium is defective in mutant embryos (B), but endothelial cells (white ovals) are present in the mutant embryos (D), suggesting that initial specification occurs properly. Arrowheads mark endothelium in A, B and endothelial cells in C, D. Based on data published in (Visvader et al., 1998).

Figure 3

Defective differentiation of arterial endothelial cells and abnormal artery development in Foxc1; Foxc2 double mutant mice at E9. Foxc1;Foxc2 double mutant mice exhibit arteriovenous malformations (white arrow in panel B) and abnormal expression of venous markers, such as COUP-TFII in arteries (C, D). The white arrow in (C) marks the dorsal aorta (da) in the wild type embryo, which expresses PECAM-1, but not COUP-TFII. The white arrowhead in (C) marks the cardinal vein (cv) in the wild type embryo, which properly expresses both PECAM-1 and COUP-TFII. The red arrow in (D) marks PECAM-1+ arterial endothelial cells, which aberrantly express COUP-TFII and other venous markers in double mutant embryos. nt, neural tube. The images shown were originally published in (Seo et al., 2006).

Figure 4

Schematic representations of mouse yolk sacs at E11 from wild type (A) and Fli1 mutant (B) embryos. Endothelial cells are properly specified and the vasculature is initially formed normally in mutant embryos. However, mutant embryos have a nearly complete absence of blood cells (circles in A), indicating a profound defect in hematopoiesis. Based on data published in (Spyropoulos et al., 2000).

Figure 5

Etv2 null mice fail to specify endothelial cells. Immunohistochemical staining for Flk1 (A, B) at E9.5 shows normal endothelial cell specification and differentiation and vessel remodeling in wild type embryos (A), whereas Etv2 (Er71) mutants have no detectable expression of Flk1 (B). Similarly, blood-filled vessels are not present in the yolk sac of Etv2 mutant embryos (D) at a stage when they are obvious in wild type controls (C, arrowheads). This is due to loss of detectable endothelial cells and profound defects in hematopoiesis. (E, F) Schematic representations of wild type (E) and Etv2 (Etsrp71) (F) mutant embryos, indicating that the endocardium is not properly specified in mutant embryos, as evidenced by the loss of expression of Endomucin and other endothelial markers (denoted in blue in E). The images shown in (A–D) were originally published in (Lee et al., 2008a). The schematic images shown in (E, F) are based on data published in (Ferdous et al., 2009).

Figure 6

Different stages in endothelial development are regulated by distinct sets of transcription factors. This model depicts the steps within endothelial cell development from mesodermal progenitors and hemangioblasts to differentiated arterial, venous, and lymphatic endothelium and the various transcription factors associated with their development. This model depicts the speculation that Fli-1, GATA2, and Tal1 control differentiation of hematopoietic cells from hemangioblasts, while Etv2 and FoxC proteins control the differentiation of endothelial cells from that progenitor population and that Etv2 likely sits at the top of this transcriptional cascade.