Netrin-1 inhibits sprouting angiogenesis in developing avian embryos

Abstract

Netrin-1 is a bifunctional axonal guidance cue, capable of attracting or repelling developing axons via activation of receptors of the deleted in colorectal cancer (DCC) and uncoordinated 5 (UNC5) families, respectively. In addition to its role in axon guidance, Netrin-1 has been implicated in angiogenesis, where it may also act as a bifunctional cue. Attractive effects of Netrin-1 on endothelial cells appear to be mediated by an as yet unknown receptor, while repulsion of developing blood vessels in mouse embryos is mediated by the UNC5B receptor. To explore evolutionary conservation of vascular UNC5B expression and function, we have cloned the chick unc5b homologue. Chick and quail embryos showed unc5b expression in arterial EC and sprouting angiogenic capillaries. To test if Netrin-1 displayed pro- or anti-angiogenic activities in the avian embryo, we grafted cell lines expressing recombinant chick or human Netrin-1 at different stages of development. Netrin-1 expressing cells inhibited angiogenic sprouting of unc5b expressing blood vessels, but had no pro-angiogenic activity at any stage of development examined. Netrin-1 also had no effect on the recruitment of circulating endothelial precursor cells. Taken together, these data indicate that vascular unc5b expression and function is conserved between chick and mice.

The Bipartite Rac1 Guanine Nucleotide Exchange Factor Engulfment and Cell Motility 1/Dedicator of Cytokinesis 180 (Elmo1/Dock180) Protects Endothelial Cells from Apoptosis in Blood Vessel Development

“…Yet, the exact biochemical mechanisms underlying this pathway remained unclear (35). Some data in the literature suggest an anti-angiogenic function of Netrin-1 and its endothelial receptor Unc5B (73,74), which is in conflict with recently published data showing a pro-angiogenic and pro-survival function of this signaling cascade (35,45,75). However, this controversy can be explained by the dependence receptor function of the Netrin receptors.…”

Vascular Development in the Zebrafish

“…Netrin1 and its receptor, UNC5B, are required for the proper vessel formation, although conflicting data exist as to whether netrin signaling plays a repulsive role Larrivee et al 2007;Bouvree et al 2008), an attractive role (Navankasattusas et al 2008), or, potentially, both (Yang et al 2007) in the developing vasculature. In addition to their role in arterialvenous specification (Herbert et al 2009), ephrins are also implicated in vascular sprouting in zebrafish.…”

Neurovascular development

“…36,37 A recent study suggests that some of these differences may be due to vascular bed specific differences, while another suggests that levels of ligand may determine positive vs. negative effects on vascular development. 38,39 Thus several molecular signaling pathways can affect both neural development and vascular development; however, deciphering any unique effects on neurovascular development and function is complex and ongoing.…”