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First published online 4 July 2007
doi: 10.1242/dev.004184

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Notch signaling in vascular development and physiology

The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.

View larger version (35K): [in this window] [in a new window]   Fig. 1. Core components of the canonical Notch signaling pathway. Ligands of the Jagged (JAG1 and JAG2) and Delta-like (DLL1, DLL3, DLL4) families (upper cell, shown in green) interact with Notch family receptors (NOTCH1 through to NOTCH4) on an adjacent cell (lower cell, shown in yellow). The Notch receptor exists at the cell surface as a proteolytically cleaved heterodimer consisting of a large ectodomain and a membrane-tethered intracellular domain. The receptor-ligand interaction induces two additional proteolytic cleavages that free the Notch intracellular domain (NICD) from the cell membrane. The NICD translocates to the nucleus (blue), where it forms a complex with the RBPJ protein, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from the RBPJ protein. Components of an activation complex, such as MAML1 and histone acetyltransferases (HAc), are recruited to the NICD-RBPJ complex, leading to the transcriptional activation of Notch target genes.

View larger version (74K): [in this window] [in a new window]   Fig. 2. Vascular defects in a Notch1-null mouse embryo. (A) Extraembryonic yolk sac from a wild-type mouse embryo exhibits remodeling of the yolk sac vasculature to generate vessels of different sizes. (B) Yolk sac from a Notch1-/-mutant mouse embryo. The yolk sac has arrested at the primitive vascular plexus stage, and has not undergone any angiogenic vascular remodeling. Both yolk sacs have been immunostained with an antibody to a protein expressed on vascular endothelial cells. Reproduced with permission from Krebs et al. (Krebs et al., 2000). Copyright (2000) Cold Spring Harbor Laboratory Press.

View larger version (33K): [in this window] [in a new window]   Fig. 3. Artery-vein differentiation. (A) Yolk sac from a wild-type (Rbpj+/+) mouse embryo, which expresses an ephrin B2-lacZ transgene, a marker of arterial differentiation. (B) Yolk sac from an Rbpj-/- mutant mouse embryo, which does not express the ephrin B2-lacZ gene. (C,D) Model for genetic regulation of artery-vein differentiation. (C) During artery differentiation, two primary signaling pathways operate downstream of Vegfa: the Notch pathway (green box) and the PLC/MAPK pathway (pink box) (Lamont and Childs, 2006). The transcription factors Foxc1 and Foxc2 induce Dll4 gene expression, but it is unknown whether Foxc1 and Foxc2 expression is regulated by Vegfa. (D) During vein differentiation, two different mechanisms inhibit artery differentiation (blue text). The orphan nuclear receptor COUP-TFII (Nr2f2) suppresses neuropilin 1 expression, thereby suppressing reception of the Vegfa signal and activation of Notch signaling. In addition, the activation of PI3K/Akt signaling antagonizes the promotion of arterial cell differentiation by blocking (blue cross) ERK activation. A and B are reproduced with permission from Krebs et al. (Krebs et al., 2004). Copyright (2004) Cold Spring Harbor Laboratory Press.

View larger version (38K): [in this window] [in a new window]   Fig. 4. Arteriovenous malformations in Notch pathway mutant mice. (A) In a wild-type embryo, India ink is injected into the heart to visualize blood flow as it exits anteriorly through the aortic arch arteries (aa) and enters the descending dorsal aorta (da). (B) In an embryo with an endothelial cell-specific deletion of the Notch1 gene (Tek-Cre/+; Notch1flox/-), arteriovenous malformations permit the injected ink to leak directly into the venous system. Original images provided by Luke Krebs in my laboratory; reproduced with permission from Weinmaster and Kopan (Weinmaster and Kopan, 2006).

View larger version (68K): [in this window] [in a new window]   Fig. 5. Notch signaling specifies arterial differentiation of vascular smooth muscle cells. (A,B) Smooth muscle myosin heavy chain (smmhc, green) expression in wild-type and Notch3-/- tail arteries. (B) Arteries of the Notch3-/- mouse exhibit normal smmhc expression levels. Arrows highlight ectopic vascular smooth muscle cells expressing smmhc in the Notch3-/- mutant artery. (C,D) Smoothelin (red) (cell nuclei are stained with DAPI, blue) expression in wild-type and Notch3-/- tail arteries. Smoothelin expression levels are markedly reduced in the Notch3-/- mutant artery (D). (E-H) ß-galactosidase staining (blue) of tails from wild-type and Notch3-/- mice heterozygous for a SM22-lacZ transgene. (E,F) Whole-mount view of caudal artery (arrows) in the tail and (G,H) microscopic view through artery (a) and vein (v) demonstrate that ß-galactosidase staining is restricted to arterial vascular smooth muscle cells in control mice and is markedly reduced in Notch3-/- arteries. Reproduced with permission from Domenga et al. (Domenga et al., 2004). Copyright (2004) Cold Spring Harbor Laboratory Press.

View larger version (90K): [in this window] [in a new window]   Fig. 6. Vascular defects in Dll4+/- retinas. Retinal vasculature at postnatal day 5 from (A) wild-type (WT) and (B) Dll4+/- mice. Note the areas of vessel fusion (arrow) and increased sprouting and branching at the leading edge (top) in the Dll4+/- retina. a, artery; v, vein. Reproduced with permission from Suchting et al. (Suchting et al., 2007). Copyright (2007) National Academy of Sciences, USA.