Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels

Abstract

Mice with targeted mutations in genes required for Notch signal transduction die during embryogenesis, displaying overt signs of hemorrhage due to defects in their vascular development. Surprisingly, directed expression of a constitutively active form of Notch4 within mouse endothelial cells produces a similar vascular embryonic lethality. Moreover, patients with mutations in Notch3 exhibit the cerebral vascular disorder, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These findings underscore the importance of Notch signaling in vascular development; however, they do not identify the specific functional defect. Here, we report that Notch1, Notch3, Notch4, Delta4, Jagged1 and Jagged2 are all expressed in arteries, but are not expressed by veins. These findings identify an aspect of Notch signaling that could contribute to the mechanism by which this pathway modulates vascular morphogenesis.

In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

“…We did, for instance, not fully explore the potential involvement of TGF-␤, COUP-TFII, adrenomedullin, or angiopoietins, known to play a role in AV fate decisions. 7,14,22,40 During development and in primary ECs, 52 Notch activation has been associated with endothelial-to-mesenchymal transformation. Despite the ability of hMAPCs to robustly differentiate into SMCs under other conditions ( Figure S1; Document S1), the conditions used for EC differentiation induced SMC differentiation of hMAPCs in vitro and in vivo to a low degree (not shown).…”

“…3 Indeed, arteriovenous (AV) specification of ECs is accomplished early in development and is associated with the expression of a specific complement of factors: venous endothelium is characterized by the expression of EphB4, 4 Lefty-1, 5 Lefty-2, 5 COUP-TFII, 6 and MYO1-␤, 5 and arterial ECs express high levels of Notch 1 and 4, 7 Dll-4, 8 EphrinB1 and EphrinB2, 4 Jagged-1 and -2, 7 connexin-40, and Hey-2 (gridlock zebrafish ortholog). 9,10 Studies in Xenopus, zebrafish, and mice have revealed that, besides blood flow, 11 vessel-intrinsic cues and-later in development-signals from outside the vasculature 12,13 are implicated in defining arterial or venous fate such as members of the TGF-␤ pathway, 14,15 VEGF isoforms, 13,[16][17][18] neuropilins, 17 angiopoietins, 19 the Notch pathway, 7,9,[20][21][22] the patched pathway, 20 and COUP-TFII, a member of the orphan nuclear receptor superfamily. 6 Although it has been shown that some of these pathways are well conserved from zebrafish to mouse, less information is available on whether they have a similar role in humans.…”

In vitro assays of angiogenesis for assessment of angiogenic and anti-angiogenic agents

“…There are differences, for example, in growth factor receptor expression between arterial and venous endothelial cells (Moyon et al, 2001;Villa et al, 2001;Wang et al, 1998); in expression of MMPs and TIMP1 between HUVEC and human dermal microvascular endothelial cells (Jackson and Nguyen, 1997); and in ecto-5′-nucleotidase activity between human and porcine endothelial cells (Smolenski et al, 2006). Different endothelial cell types may behave differently in cell culture assays.…”

Différenciation artérioveineuse : génétique ou hémodynamique ?

“…Toutes sont également exprimées dans le système nerveux où elles contrô-lent la destinée et le guidage des précur-seurs neuronaux et des axones, ce qui suggère leur rôle dans l'établissement du réseau vasculaire. Les CE artérielles du poisson zèbre, du poulet et de la souris expriment sélectivement l'éphrine-B2, la neuropiline 1 (NRP1), le récepteur notch3, le ligand de Notch Delta-like 4 et gridlock [5][6][7][8][9][10][11][9][10][11][12][13][14][15][16]. D'autres molécules sont spécifiquement exprimées par les CE veineuses, notamment EphB4, le récepteur du marqueur artériel éphrine-B2 [12].…”