Regulation of endothelial cell differentiation and specification

Abstract

The circulatory system is the first organ system to develop in the vertebrate embryo and is critical throughout gestation for the delivery of oxygen and nutrients to, as well as removal of metabolic waste products from, growing tissues. Endothelial cells, which constitute the luminal layer of all blood and lymphatic vessels, emerge de novo from the mesoderm in a process known as vasculogenesis. The vascular plexus that is initially formed is then remodeled and refined via proliferation, migration, and sprouting of endothelial cells to form new vessels from preexisting ones during angiogenesis. Mural cells are also recruited by endothelial cells to form the surrounding vessel wall. During this vascular remodeling process, primordial endothelial cells are specialized to acquire arterial, venous, and blood-forming hemogenic phenotypes and functions. A subset of venous endothelium is also specialized to become lymphatic endothelium later in development. The specialization of all endothelial cell subtypes requires extrinsic signals and intrinsic regulatory events, which will be discussed in this review.

Figure 1

Major extrinsic and intrinsic factors that regulate endothelial cell specification throughout embryonic vascular development

Figure 2. Retinoic acid (RA) is produced by the visceral endoderm (VE) and initiates a signaling cascade that regulates control of endothelial cell cycle proliferation

(Illustration credit: Ben Smith).

Figure 3. Parallel development of blood and blood vessels in early vertebrate embryos

A. In the extraembryonic yolk sac (YS), aggregates of mesodermal cells form blood islands composed primitive erythroid cells and angioblasts during the late gastrulation phases (E7.0). A primitive vascular plexus is soon formed by coalescence of blood islands, and by the time definitive hematopoietic development is initiated (E8.25), the vascular plexus is beginning to be remodeled into a vascular network comprised of large vitelline veins as well as smaller, pruned vessels. Definitive hematopoiesis is marked by the generation of multiple, if not all, blood cells lineages from hemogenic endothelial cells, which give rise to blood clusters initially observed in the yolk sac tissues and later intraembryonically, on the ventral side of the aorta-gonads-mesonephros region (AGM) (as early as E9.5). B. Intrinsic and extrinsic factors that regulate hemogenic endothelium specification and HSPC development. Phenotypic markers that define relevant cell subpopulations during definitive hematopoiesis are also indicated. (Illustration credit: Ben Smith).