Figure 6. A model depicting the Shh-VEGF-Notch-Hey2 pathway in LPM angioblast proliferation.

This model is based on data from here and from other groups [12], [14], [37], [38], [40], [41], [55]. Nomenclature for the various structures, molecules and cell types are indicated. Starting at 3 som, sonic hedgehog (shh) or other signal from the notochord stimulate VEGF₁₂₁ expression from adjoining hypochord, which is associated with endoderm cells lining the yolk boundary. At 4–8 som, VEGF₁₂₁ diffuses via intermediate mesoderm and contacts angioblast cells that are positive for etsrp and flk marker. At 9 som, a second source of VEGF from somite is detected, which is likely induced by shh from Notochord. Whether the two sources of VEGF have similar or different function is unknown. At approximately 10 som, the VEGF binding to its receptor (Flk?) triggers Notch activation at the LPM [12], which results in activation of downstream target genes such as hey2/gridlock. We hypothesize that this signal activation triggers angioblast proliferation at the LPM. A second feedback loop of hey2-VEGF between hey2 angioblast and VEGF in somite or in hypochord exists, but the temporal and spatial function of this loop is yet to be determined. NO: notochord, NT: neural tube, S: somite.