Netrin-1 role in angiogenesis: To be or not to be a pro-angiogenic factor?

Abstract

A ngiogenesis designates the formation of new vessels from preexisting ones, and occurs mainly during development. Tight control of this process is a prerequisite to avoid excess/defect in angiogenesis that are the underlying causes of several diseases conditions. Growing lines of evidences have indicated that some guidance cues are involved in regulation of vascular system elaboration, in addition to their role during nervous system development. In this way, netrin-1 has been involved in control of angiogenesis. However, a controversy has emerged regarding its action, since it was concluded from different studies that this protein was either a pro or an antiangiogenic factor. Thus, netrin-1 role is still unclear. The aim of this review is to propose clues to explain previously reported discrepancies, in light of the dependence receptors model. Indeed, netrin-1 could likely favor angiogenesis, notably by blocking apoptosis induced by its unbound UNC5B receptor.

Netrin 1 contributes to vascular remodeling in the subventricular zone and promotes progenitor emigration after demyelination

“…These results underline a specific role for NTN1 in lesion-induced SVZ reactivity. Several groups have highlighted the influence of NTN1 on angiogenesis both in vitro and during development (Navankasattusas et al, 2008;Park et al, 2004;Wilson et al, 2006;Fan et al, 2008;Castets and Mehlen, 2010). We demonstrate here that NTN1 injection in the lateral ventricle of adult mice is sufficient to trigger angiogenesis in the SVZ.…”

Placental labyrinth formation in mice requires endothelial FLRT2–UNC5B signaling

“…However, Ntn1 knockout mice survive until birth and have no vascular abnormalities (Yung et al, 2015), indicating that netrin 1 is not necessarily the only ligand for UNC5B, and an absence of netrin 1 might be compensated for by other ligands in vivo, specifically roundabout homolog 4 or netrin 4 (Koch et al, 2011;Lejmi et al, 2008;Li et al, 2012). Conflicting reports exist regarding the role of netrin 1 as either a pro-angiogenic or antiangiogenic factor (Lu et al, 2004;Larrivée et al, 2007;Wilson et al, 2006;Castets and Mehlen, 2010). One argument that appears to resolve this dilemma is the ability of netrin 1 to block apoptosis that would otherwise be induced by unbound UNC5B receptors, thus promoting the survival of endothelial cells during angiogenesis (Castets et al, 2009).…”

“…Indeed, proteolytic fragments of netrin 1 bind UNC5B in diabetic endothelial cells and increase vascular permeability (Miloudi et al, 2016). However, in terms of developmental angiogenesis, the situation regarding the role of netrin 1/UNC5B signaling is complex and has been subject to debate; notably, the abnormalities reported for UNC5B-deficient mice are absent in netrin 1 mutants (Serafini et al, 1996;Wilson et al, 2006;Castets and Mehlen, 2010;Yung et al, 2015). Our results suggest that FLRT2 is the predominant ligand that is associated with the role of UNC5B in vascular development and indicate that fine-tuning of vascular morphogenesis by interendothelial repulsion contributes crucially to the development of the placental labyrinth.…”

Netrin-1 induced activation of Notch signaling mediates glioblastoma cell invasion

“…Recently it was observed to function more widely during embryogenesis by regulating the branching morphogenesis of the mammary gland, pancreas and lungs (Liu et al, 2004;Srinivasan et al, 2003;Yebra et al, 2003). In addition, it regulates both developmental and pathological angiogenesis (reviewed by Castets and Mehlen, 2010).…”