Extrinsic Notch Ligand Delta-Like 1 Regulates Tip Cell Selection and Vascular Branching Morphogenesis

Abstract

Key Words: blood vessels Ⅲ development Ⅲ mouse, mutant strains Ⅲ branching Ⅲ tip cells Ⅲ Delta-like ligand 1 Ⅲ Notch B lood vessels form 3-dimensional branched networks whose architecture is tailored to serve specific physiological functions in different organs. 1 Retinal angiogenesis begins at birth with the formation of a superficial primary plexus (PP), which spreads by angiogenic sprouting from the center to the periphery on the surface of the ganglion cell layer. Subsequently, vessels branch vertically into the deeper layers of the retina to establish a secondary plexus, which supplies the retinal neurons. 2 During PP development, single endothelial cells (ECs) specialize into motile endothelial tip cells that locate at the leading edge of growing angiogenic sprouts and contribute to vessel branching by sensing guidance cues, such as vascular endothelial growth factor (VEGF) gradients, in the extracellular milieu. 3 Tip cell formation in the sprout is tightly regulated by the Notch signaling pathway, a cell contact-dependent signaling mechanism activated by binding of Notch receptors to ligands of the conserved Delta-like (Dll) and Jagged (Jag) gene families ( Figure 4E). 4 The ligand Dll4 is upregulated by VEGF in selected ECs in the angiogenic front, which behave as tip cells and activate Notch receptors in adjacent stalk ECs, thereby suppressing a tip cell phenotype and angiogenic sprouting. In contrast, the ligand Jag1 is strongly expressed in stalk ECs and antagonizes Dll4 function and tip cell suppression, which shows that endothelium-intrinsic Notch signaling regulates tip cell formation. 5 However, induction of Dll4 by VEGF is Notch dependent, which raises the possibility that extrinsic Notch ligands contribute to tip cell selection. 6 The Notch ligand Dll1Original received December 19, 2011; revision received January 4, 2012; accepted January 17, 2012. In December 2011, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.29 days.Brief UltraRapid Communications are designed to be a format for manuscripts that are of outstanding interest to the readership, report definitive observations, but have a relatively narrow scope. In This Issue, see p 523 MethodsVertical branching was studied in isolectin B4 -stained frontal cross sections from the posterior parts of the retina from isogenic 129S1/ SvImJ-background littermates. Detailed Methods are discussed in the online-only Data Supplement. ResultsIn mice with heterozygous Dll1 loss of function, which showed no overt developmental or postnatal phenotype (Online Figure I), tip cell numbers and plexus complexity were decreased significantly ( Figure 1A), and expansion of the PP was partially disturbed ( Figure 1B). Analysis of deep plexus angiogenesis in retina cross sections revealed that vertical branch development was delayed and strongly reduced in Dll1 ϩ/Ϫ retinas at all neonatal stages investigated ( Figures 1C and 1D). Furthermore, expansion of the deep plexus was also impa...

Selective regulation of Notch ligands during angiogenesis is mediated by vimentin

“…Aortic rings from mice lacking vimentin produce fewer sprouts compared with WT mice and sprouting is rescued by reactivating Jaggedmediated Notch signaling by recombinant ligands immobilized within the collagen matrix in which the aortic rings are embedded. These results add to the current view of the effect of these ligands on angiogenesis (31,59). Jagged has been suggested to counteract Dll4 signaling through cis-inhibition by direct binding to the Notch receptors and inhibition of Dll4-mediated activation in the signal receiving cell (35,60,61).…”

Can maternal DHA supplementation offer long-term protection against neonatal hyperoxic lung injury?

“…However, no differences were found in the levels of NICD by the authors. DLL1 is an essential Notch ligand, and DLL1-mediated Notch activation is crucial for postnatal arteriogenesis and vascular morphogenesis (21,30). Decreased DLL1 (as found in this study)-mediated Notch activation would be expected to decrease postnatal pulmonary blood vessel development.…”

Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a

“…There is a high expression of DLL4 in endothelial tip cells; this protein then interacts with Notch1 receptors in neighboring endothelial cells, and thereby prevents the those endothelial cells from being specified as tip cells and, hence, suppresses angiogenesis (Sainson et al, 2005). Recent studies also show that inhibition of DLL4-Notch signaling increases the number of the endothelial cells committed to the tip cell fate and augments tube branch density (Leslie et al, 2007;Niessen et al, 2011;Napp et al, 2012). Hence, we considered that adMSC-Exo and exosomal transferred miR-125a might promote angiogenesis through induction of endothelial tip cell formation.…”