Notch signaling in the vasculature - PubMed (original) (raw)

Review

Notch signaling in the vasculature

Thomas Gridley. Curr Top Dev Biol. 2010.

Abstract

Notch signaling is an evolutionarily conserved, intercellular signaling mechanism that plays myriad roles during vascular development and physiology in vertebrates. These roles include the regulation of arteriovenous specification and differentiation in both endothelial cells and vascular smooth muscle cells, regulation of blood vessel sprouting and branching during normal and pathological angiogenesis, and the physiological responses of vascular smooth muscle cells. Defects in Notch signaling also cause inherited vascular diseases, such as the degenerative vascular disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. This review summarizes recent studies that highlight the multiple roles the Notch signaling pathway plays during vascular development and physiology.

Copyright © 2010 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Core components of the canonical Notch signaling pathway

Ligands of the Jagged (JAG1, JAG2) and Delta-like (DLL1, DLL3, DLL4) families (upper cell) interact with Notch family receptors (NOTCH1 through NOTCH4) on an adjacent cell. 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 Fringe proteins (Lfng, Mfng and Rfng) glycosylate Notch family receptors, potentiating signaling from DLL family ligands and suppressing signaling from JAG family ligands. The receptor/ligand interaction induces additional proteolytic cleavages in the membrane-tethered intracellular domain. The final cleavage, catalyzed by the γ–secretase complex, frees the Notch intracellular domain (NICD) from the cell membrane. NICD translocates to the nucleus, where it forms a complex with the RBPJ protein, displacing a histone deacetylase (HDAc)/corepressor (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.

Figure 2

Figure 2. Model for genetic regulation of artery-vein differentiation by the Notch and PLCγ/MAPK pathways

An arterial endothelial cell is shown on the left, while a venous endothelial cell is depicted on the right. Two main signaling pathways operate downstream of VEGF-A to induce arterial differentiation: the Notch pathway and the Phospholipase Cγ (PLCγ) / Mitogen-activated protein kinase (MAPK) pathway. The transcription factors Foxc1 and Foxc2 directly induce Dll4 and Hey2 transcription. VEGF-A signaling, by an unknown mechanism, augments Foxc1/Foxc2 induction of Dll4 and Hey2 gene expression. During venous differentiation, two different mechanisms inhibit artery differentiation. The orphan nuclear receptor COUP-TFII suppresses neuropilin1 expression, thereby suppressing reception of the VEGF-A signal and activation of Notch signaling. In addition, activation of PI3K/Akt signaling antagonizes promotion of arterial cell differentiation by blocking ERK activation.

Figure 3

Figure 3. Antagonistic roles of the DLL4 and JAG1 proteins in tip cell selection during sprouting angiogenesis

An endothelial tip cell (white) at the leading edge of a vascular sprout extends filopodia and migrates towards a VEGF-A gradient. Signal reception by VEGF receptors (VEGFRs) in the tip cell leads to upregulation of DLL4 expression (Inc DLL4). The tip cell signals via DLL4 to the adjacent Notch receptor-expressing cell, downregulating VEGF receptor expression. This suppresses the tip cell fate and promotes differentiation of the adjacent endothelial cell as a stalk cell (gray). Glycosylation of Notch receptors (likely NOTCH1) by Fringe proteins enhances DLL4-Notch signaling and suppresses JAG1-Notch signaling. The DLL4 and JAG1 ligands act in an antagonistic fashion during endothelial tip cell selection and angiogenic sprouting. DLL4, expressed more highly on tip cells, suppresses adoption of the tip cell fate and angiogenic sprouting. JAG1, which is expressed more highly on stalk cells, promotes tip cell differentiation and sprouting behavior by antagonizing DLL4-Notch signaling between stalk cells.

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