Signal transduction in vasculogenesis and developmental angiogenesis

Abstract

The vasculature is a highly specialized organ that functions in a number of key physiological tasks including the transport of oxygen and nutrients to tissues. Formation of the vascular system is an essential and rate-limiting step in development and occurs primarily through two main mechanisms, vasculogenesis and angiogenesis. Both vasculogenesis, the de novo formation of vessels, and angiogenesis, the growth of new vessels from pre-existing vessels by sprouting, are complex processes that are mediated by the precise coordination of multiple cell types to form and remodel the vascular system. A host of signaling molecules and their interaction with specific receptors are central to activating and modulating vessel formation. This review article summarizes the current state of research involving signaling molecules that have been demonstrated to function in the regulation of vasculogenesis and angiogenesis, as well as molecules known to play a role in vessel maturation, hypoxia-driven angiogenesis and arterial-venous specification.

Figure 1. Schematic of extra-embryonic vasculogenesis

(A) Endodermal cells (orange) induce mesodermal cells (aqua), initiating vasculogenesis. (B) Hemangioblasts migrate and associate. (C) Blood islands containing centrally located hematopoietic precursor cells (purple) and peripherally localized angioblasts (blue) are formed. (D) Angioblasts differentiate to endothelial cells (blue) and hematopoietic cells (red) further differentiate. (E) Lumenization occurs, tight junctions (dark blue dashes) form between endothelial cells and a basement membrane (green) is deposited along the basolateral endothelial cell surface. The association of pericytes (magenta) is correlated with the deposition of the basement membrane and marks vessel maturation.

Figure 2. VEGF receptors and their ligands

VEGFR-1 (orange), VEGFR-2 (blue) and VEGFR-3 (green) are depicted. Ligands known to activate the receptors are displayed above each receptor. Neuropilins-1 (red) and -2 (purple), co-receptors for VEGF receptors, are also shown adjacent to the receptors with which they associate.

Figure 3. The VEGFR-2 signaling cascade and effects

The VEGFR-2 homodimer (blue) and its phosphorylated residues known to facilitate signaling are shown. Proteins that bind to VEGFR-2 are depicted (green) along with their downstream targets (purple). Phosphorylation of VEGFR-2 Tyr1054 and Tyr1059 residues are required for maximal receptor activation. Binding of TsAd to phosphorylated residue Tyr951 enhances endothelial cell migration and vascular permeability through Src activation. Phosphorylation of residue Tyr1175 recruits PLCγ, which activates PKC to activate endothelial cell proliferation and migration through PKD or the MAPK pathways. Tyr1175 is also a docking site for Shb, which activates endothelial cell migration or endothelial cell survival through the PI3K and AKT/PKB pathway. Phosphorylation of Tyr1214 subsequently activates cdc42 and p38 MAPK to induce endothelial cell migration. Finally, phosphorylation of VEGFR-2 also activates FAK and paxillin and IQGAP to stimulate endothelial cell motility. Abbreviations: VEGFR-2 (vascular endothelial growth factor receptor-2); TsAd (T-cell specific adaptor); Tyr (tyrosine); FAK (focal adhesion kinase), IQGAP1 (IQ motif containing GTPase activating protein 1); PLCγ (phospholipase C gamma); Shb (Src homology 2 and β cells); PKC (protein kinase C); MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase); MAPK (mitogen-activated protein kinase); PKD (protein kinase D); HDAC7 (histone deacetylase 7); PI3K (phophatidylinositol 3′-kinase); PKB (protein kinase B); eNOS (endothelial nitric oxide synthase)