VEGF-directed blood vessel patterning: from cells to organism

Abstract

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.

Figure 1.

Alternative splicing of VEGF-A and VEGFR-1 (Flt-1) leads to distinct isoforms. (A) Alternative splicing of the initial transcript from the VEGF-A locus leads to three major VEGF-A isoforms (minor isoforms not shown): VEGF121, VEGF165, and VEGF189 (in mouse, VEGF120, VEGF164, and VEGF188). Exons 6 and 7 have heparin-binding domains, thus each major isoform has a different capacity for matrix interactions. (B) Alternative splicing of VEGFR-1 (Flt-1) leads to the two protein isoforms shown here. mFlt-1 is membrane-tethered, whereas sFlt-1 is secreted from the cell. Both Flt-1 isoforms have heparin-binding capability. Blue sections are shared by both isoforms, the red section is specific to sFlt-1, and purple sections are specific to mFlt-1.

Figure 2.

Model of spatial organization of VEGF-A signaling components. VEGF-A is released from a source (top of figure) and, owing to isoform-specific differences in matrix interactions, forms a gradient (green areas) from the source to the target vessel. Some endothelial cells respond to this signal by acquiring a tip cell (red cell) identity and migrating up the gradient, whereas adjacent lateral base cells (orange cells) up-regulate Flt-1 (VEGFR-1) and secrete soluble Flt-1 (blue areas) that inactivates VEGF-A in the lateral areas, providing a corridor of ligand for effective outward migration of the sprout. (Green icons) VEGF-A protein; (blue receptors) membrane-localized and soluble Flt-1.

Figure 3.

Blood vessel polarity. Blood vessels polarize in the apical (luminal) versus basolateral (abluminal) planes, and in the plane of the tube (planar cell polarity). (Right panel) The mouse P5 retinal vessel stained with isolectin B4 (red) after perfusion fixation with the same lectin (labeled in green). Arrows point to membranes that have both labels and are likely to be the apical surfaces, and the inset in the upper right shows a Z-stack projection.