Notch Signaling in Primary Endothelial Cells

Shawber, Carrie J.; Das, Ira; Francisco, Esther; Kitajewski, Jan

doi:10.1111/j.1749-6632.2003.tb03219.x

Cited by 85 publications

(81 citation statements)

References 29 publications

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“…Furthermore, the mRNA level of Notch1, which is expressed primarily in ECs in the liver (24), was slightly increased. Our results are consistent with in vitro studies that show that expression of int3 leads to the up-regulation of Dll4 in cultured ECs (25) and demonstrate that int3 can up-regulate the expression of endogenous Notch pathway genes in vivo.…”

Section: Up-regulation Of Notch Pathway Gene Expression In the Mutantsupporting

confidence: 92%

Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice

Carlson

Yan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

177

213

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Direct communication between arteries and veins without intervening capillary beds is the primary pathology of arteriovenous malformations (AVMs). Although Notch signaling is implicated in embryonic arteriovenous (AV) differentiation, its function in the adult mammalian vasculature has not been established due to the embryonic lethality that often occurs in both gain- and loss-of-function mutants. We expressed a constitutively active Notch4, int3, in the adult mouse endothelium by using the tetracycline-repressible system to suppress int3 during embryogenesis. int3 caused profound blood vessel enlargement and AV shunting, which are hallmarks of AVM, and led to lethality within weeks of its expression. Vessel enlargement, a manifestation of AVM, occurred in an apparently tissue-specific fashion; the liver, uterus, and skin were affected. int3-mediated vascular defects were accompanied by arterialization, including ectopic venous expression of ephrinB2, increased smooth muscle cells, and up-regulation of endogenous Notch signaling. Remarkably, the defective vessels and illness were reversed upon repression of int3 expression. Finally, endothelial expression of a constitutively active Notch1 induced similar hepatic vascular lesions. Our results provide gain-of-function evidence that Notch signaling in the adult endothelium is sufficient to render arterial characteristics and lead to AVMs

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Section: Up-regulation Of Notch Pathway Gene Expression In the Mutantsupporting

confidence: 92%

Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice

Carlson

Yan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

177

213

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“…Neuropilin-1 (NRP-1) is also expressed strongly in arterial EC but only weakly in venous EC (Herzog et al, 2001;Moyon et al, 2001). Furthermore, activation of the Delta-Notch pathway in arterial EC was indicated to be critical for upregulation of the expression of the ephrinB2 and NRP-1 genes in arterial EC (Shawber et al, 2003). Therefore, the DeltaNotch pathway is a good candidate for the transcriptional activator of I-Smad genes in arterial EC.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Smad transcription factors protect arterial endothelial cells from apoptosis induced by BMP4

Kiyono

Shibuya

2006

Oncogene

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Arterial endothelial cells (EC) at the adult stage differ from capillary and venous EC in terms of resistance to stress; however, the molecular basis of this resistance is not clear. Here, we found that arterial EC are highly resistant to bone morphogenetic protein (BMP)4-dependent apoptosis, whereas capillary and venous EC are not. The expression of inhibitory Smads (I-Smads) in arterial EC was well correlated with the resistance to this apoptosis. After the knockdown of I-Smad expression by short interfering RNA, the resistant arterial EC became sensitive to BMP4. In contrast, the ectopic expression of I-Smads in BMP4-sensitive cells suppressed BMP4-induced apoptosis. Furthermore, intravenous administration of BMP4 into mice caused hemorrhage of capillary EC in brain and lung. These results strongly suggest that BMP4/I-Smads are a novel regulator for the stability of vascular EC.

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“…Activated NOTCH Signaling Induces DLL4 Expression by Activating DLL4 Promoter-NOTCH-1 and NOTCH-4 are the main mediators of NOTCH signaling in the endothelium (28,29). To define the direct effect of NOTCH signaling on DLL4 expression, HCMvECs were transfected with the intracellular domain of NOTCH-1 and -4 (NICD-1 and NICD-4, respectively) or empty vector.…”

Section: Vegfr2-mediated Dll4 Expression Involves Notch Signaling In mentioning

confidence: 99%

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Caolo

Akker

Verbruggen

et al. 2010

Journal of Biological Chemistry

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The DELTA like-4 ligand (DLL4) belongs to the highly conserved NOTCH family and is specifically expressed in the endothelium. DLL4 regulates crucial processes in vascular growth, including endothelial cell (EC) sprouting and arterial specification. Its expression is increased by VEGF-A. In the present study, we show that VEGF-induced DLL4 expression depends on NOTCH activation. VEGF-induced DLL4 expression was prevented by the blockage of NOTCH signaling with ␥-secretase or ADAM inhibitors in human cardiac microvascular ECs. Similar to VEGF-A, recombinant DLL4 itself stimulated NOTCH signaling and resulted in up-regulation of DLL4, suggesting a positive feed-forward mechanism. These effects were abrogated by NOTCH inhibitors but not by inhibition of VEGF signaling. NOTCH activation alone suffices to induce DLL4 expression as illustrated by the positive effect of NOTCH intracellular domain (NICD)-1 or -4 overexpression. To discriminate between NICD/RBP-J and FOXC2-regulated DLL4 expression, DLL4 promoter activity was assessed in promoter deletion experiments. NICD induced promoter activity was dependent on RBP-J site but independent of the FOXC2 binding site. Accordingly, constitutively active FOXC2 did not affect DLL4 expression. The notion that the positive feed-forward mechanism might propagate NOTCH activation to neighboring ECs was supported by our observation that DLL4-eGFP-transfected ECs induced DLL4 expression in nontransfected cells in their vicinity. In summary, our data provide evidence for a mechanism by which VEGF or ligand-induced NOTCH signaling up-regulates DLL4 through a positive feedforward mechanism. By this mechanism, DLL4 could propagate its own expression and enable synchronization of NOTCH expression and signaling between ECs.The NOTCH family encompasses a fundamental signaling pathway involving four receptors (NOTCH-1, -2, -3, and -4) and, in vertebrates, five cognate ligands (DLL-1, -3, and -4, and JAGGED-1 and -2). Cell-cell contact is a prerequisite for NOTCH signaling as all members are membrane bound. The first activation step upon receptor-ligand interaction involves cleavage of the extracellular domain of the NOTCH receptor by ADAM (a disintegrin and metalloprotease). Subsequently, the ␥-secretase complex instigates a second proteolytic cleavage resulting in the release of the NOTCH intracellular domain (NICD) 2 into the cytoplasm. Next, the NICD translocates to the nucleus, where it associates with the Recombinant signal binding protein for immunoglobulin kappa J region (RBP-J) CBF1/RBP-J, Su(H), Lag1 (CSL) transcription factor to initiate the transcription of its downstream targets basic helix-loop-helix proteins HES (hairy/enhancer of split) and hairy related transcription factors (HRT, HEY, and

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Notch Signaling in Primary Endothelial Cells

Cited by 85 publications

References 29 publications

Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice

Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice

Inhibitory Smad transcription factors protect arterial endothelial cells from apoptosis induced by BMP4

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

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