Notch Ligand Delta-Like 1 Is Essential for Postnatal Arteriogenesis

Abstract

Abstract-Growth of functional arteries is essential for the restoration of blood flow to ischemic organs. Notch signaling regulates arterial differentiation upstream of ephrin-B2 during embryonic development, but its role during postnatal arteriogenesis is unknown. Here, we identify the Notch ligand Delta-like 1 (Dll1) as an essential regulator of postnatal arteriogenesis. Dll1 expression was specifically detected in arterial endothelial cells, but not in venous endothelial cells or capillaries. During ischemia-induced arteriogenesis endothelial Dll1 expression was strongly induced, Notch signaling activated and ephrin-B2 upregulated, whereas perivascular cells expressed proangiogenic vascular endothelial growth factor, and the ephrin-B2 activator EphB4. In heterozygous Dll1 mutant mice endothelial Notch activation and ephrin-B2 induction after hindlimb ischemia were absent, arterial collateral growth was abrogated and recovery of blood flow was severely impaired, but perivascular vascular endothelial growth factor and EphB4 expression was unaltered.In vitro, angiogenic growth factors synergistically activated Notch signaling by induction of Dll1, which was necessary and sufficient to regulate ephrin-B2 expression and to induce ephrin-B2 and EphB4-dependent branching morphogenesis in human arterial EC. Thus, Dll1-mediated Notch activation regulates ephrin-B2 expression and postnatal arteriogenesis. (Circ Res. 2007;100:363-371.)

Systems biology approach to identify alterations in the stem cell reservoir of subcutaneous adipose tissue in a rat model of diabetes: effects on differentiation potential and function

“…Several studies have shown a role of the Notch and Wnt pathways in angiogenesis [42][43][44]. Notch signalling is required for angiogenesis in ischaemia models, and Dll1, the expression of which was lower in ASCs ZDF , is essential for postnatal angiogenesis [45], while jagged-1 (Jag1), which we also found downregulated, enhances angiogenesis [46]. Recent reports have underlined the important role of the Wnt system in vascular morphogenesis and in organ-specific EC differentiation [47].…”

Regulation of vascular morphogenesis by Notch signaling

“…In the vasculature, Dll1 is largely confined to the arterial endothelium, and expression is strongly upregulated during ischemia-induced arteriogenesis (Beckers et al 1999;Limbourg et al 2007). Postnatal functional studies in null mutants are precluded by the embryonic lethality of Dll1 knockout mice (Hrabe de Angelis et al 1997).…”

Distinct Notch signaling outputs pattern the developing arterial system

“…In addition to its requirement for vascular development, Notch signaling is also essential for vessel homeostasis in the adult. For example, similar to Delta-like 4 (Dll4) in the embryonic vasculature, Dll1 is restricted to arterial endothelial cells in adult blood vessels, where it is required for collateral artery remodeling (Limbourg et al, 2007). Thus, Notch signaling plays a number of roles within endothelial cells to govern artery differentiation, angiogenesis, and vascular homeostasis during both embryonic and adult stages.…”