VEGF and endothelial guidance in angiogenic sprouting

Abstract

The cellular actions of VEGF need to be coordinated to guide vascular patterning during sprouting angiogenesis. Individual endothelial tip cells lead and guide the blood vessel sprout, while neighbouring stalk cells proliferate and form the vascular lumen. Recent studies illustrate how endothelial DLL4/NOTCH signalling, stimulated by VEGF, regulates the sprouting response by limiting tip cell formation in the stalk. The spatial distribution of VEGF, in turn, regulates the shape of the ensuing sprout by directing tip cell migration and determining stalk cell proliferation.

Keywords: Notch; VEGF; angiogenesis; tip cells; vascular patterning.

Figure 1

Schematic illustration of the cellular mechanisms that pattern vascular sprouting. (A) Graded distribution of VEGF; sequential steps from left to right illustrate the induction of a tip cell (green) by VEGF (orange), polarization of a tip cell with rapid directed migration (blue arrow, left panel), and proliferation (pink nuclei) of the stalk cells (white). Polarization of the tip cell in a steep VEGF gradient leads to long, directed filopodia extension towards higher VEGF concentration. Polarized proliferation occurs with the division axis perpendicular to the long axis of the vessel. The pulling tip cell likely helps to polarize the stalk cell division. (B) Diffuse distribution of VEGF, like in Vegfa120/120 mice, leads to the undirected extension of short filopodia extension, although tip cell induction does occur. Tip cell migration is slow and many stalk cells proliferate due to widespread VEGF. Stalk cell proliferation is not polarized, causing vessel dilation/hypertrophy. (C) Loss of DLL4/NOTCH signaling leads to excessive sprouting through increased tip cell numbers. NOTCH signaling normally inhibits the tip cell response in stalk cells. Tip cell numbers further increase through slightly elevated proliferation.