Loss of Notch signalling induced by Dll4 causes arterial calibre reduction by increasing endothelial cell response to angiogenic stimuli

The current detailed analysis of these mutants shows that the arterial defect precedes the initiation of blood flow and that the arterial Dll4-/- endothelial cells proliferate and migrate more actively. Dll4-/- mutants reveal a defective basement membrane around the forming aorta and increased endothelial cell migration from the dorsal aorta to peripheral regions, which constitute the main causes of arterial lumen reduction in these embryos. The increased proliferation and migration of Dll4-/- endothelial cells was found to coincide with increased expression of the receptors VEGFR-2 and Robo4 and with downregulation of the TGF-β accessory receptor Endoglin.Together, these results strongly suggest that Notch signalling can increase arterial stability and calibre by decreasing the response of arterial endothelial cells to local gradients of pro-angiogenic factors like VEGF.The initial steps of embryonic blood vessel formation (vasculogenesis) involve differentiation and aggregation of mesodermal-derived endothelial precursors (angioblasts) to generate the primary vascular plexus. Blood vessels then grow and remodel into a mature network of hierarchically organized vessels, in a process designated as angiogenesis. During this remodelling, endothelial vessels differentiate into arteries and veins, grow, sprout, split and fuse according to a combination of autocrine signalling and cues provided by other tissues of the embryo [1].The formation of the initial vascular plexus is highly dependent on vascular endothelial growth factor (VEGF-A) and its receptors, VEGFR-1 and VEGFR-2, since mouse embryos lacking these genes display very early vascular defects and die between 8.5–9.5 dpc [2-4]. Notably, VEGF haploinsufficiency causes embryonic lethality. VEGFR-2 is thought to be the major mediator of the VEGF signalling since VEGFR-2-/- embryos fail to form blood islands or organized blood vessels [3], whereas VEGFR-1-/- embryos form blood vessels with an excess of endothelial a