VEGF-Directed Blood Vessel Patterning: From Cells to Organism

VEGF-A signaling is required for almost every aspect of vascular development, and it is a major regulator of vessel morphogenesis and patterning.VEGF-A perturbations are associated with severe vascular defects and lethality, and the pathway is coopted in pathological scenarios, including tumor angiogenesis.This review focuses on the roles of VEGF-A signaling during vessel development and patterning.I review the impact of VEGF-A signaling on endothelial cells in developing vessels, with emphasis on the importance of spatial regulation of several pathway components.I also discuss VEGF-A signaling patterns at the level of the vessel, with a focus on how polarity is set up and maintained in several vessel axes.The role of VEGF-A in patterning vessels relative to tissues and organs is also reviewed, with emphasis on neurovascular patterning and patterning at the embryonic midline.V EGF-A (vascular endothelial growth factor, VEGF) is important for almost every aspect of blood vessel formation and function.VEGF-A is required developmentally for the differentiation and/or expansion of angioblasts, the major precursor of endothelial cells.It is critical for the survival of endothelial cells, and the angiogenic expansion of primitive vessels via sprouting requires VEGF-A signaling.It also regulates barrier function in mature vessels.Other members of the VEGF family have roles in lymphangiogenesis and/or in pathological angiogenesis.My goal is to focus on the role of VEGF-A (VEGF) in blood vessel patterning and network formation.Thus, I will briefly outline the VEGF proteins and receptors that are relevant to vessel patterning, then discuss how VEGF patterns vessels at three levels-that of the cell, the vessel, and the tissue/organism.The cellular effects of VEGF on vessel development cover spatial heterogeneity in VEGF presentation and signaling, the role of the VEGF receptor Flt-1, and the role of VEGF isoforms and matrix in this process.The mechanisms used by the VEGF pathway are compared and contrasted with other pathways that regulate morphogenesis in other developing models.At the level of the vessel, the polarity of vascular endothelial cells that is required for lumen formation, the polarization to shear stress, and the polarization of endothelial divisions to affect vessel shape are discussed.Next, how VEGF signaling is used to set up patterning at the level of tissues and organisms is covered, with a focus on midline and neural tube patterning.