Functional Arterial and Venous Fate Is Determined by Graded VEGF Signaling and Notch Status During Embryonic Stem Cell Differentiation

Lanner, Fredrik; Sohl, Marcus; Farnebo, Filip

doi:10.1161/01.atv.0000255990.91805.6d

Cited by 86 publications

(95 citation statements)

References 28 publications

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“…In addition, NOTCH signaling alone was sufficient to induce DLL4 expression as shown by NICD-1 and NICD-4 overexpression. A comparable effect of VEGF-Ainduced DLL4 expression was described for embryonic (33) and human bone marrow-derived mesenchymal stem cells (4).…”

Section: Discussionsupporting

confidence: 66%

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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Section: Discussionsupporting

confidence: 66%

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Caolo

Akker

Verbruggen

et al. 2010

Journal of Biological Chemistry

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“…Notch, which is selectively expressed in arterial endothelial cells and acts as a downstream effector of VEGF-induced arterialization signal (Lawson et al 2001Weinstein and Lawson 2002;Lanner et al 2007;Siekmann and Lawson 2007), represses the expression of COUP-TFII, Prox1, and podoplanin through Hey1 . COUP-TFII, a nuclear receptor that is selectively expressed in the venous compartment, has been shown to interact physically and functionally with Prox1 in LECs to direct a developmental program that specifies LEC fate Yamazaki et al 2009;Kang et al 2010;Srinivasan et al 2010).…”

Section: Plasticity Of Lymphatic Endothelial Cell Fate-lymphatic Equimentioning

confidence: 99%

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi

Lee²,

Hong

2012

Cold Spring Harbor Perspectives in Medicine

118

107

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The blood and lymphatic systems are the two major circulatory systems in our body. Although the blood system has been studied extensively, the lymphatic system has received much less scientific and medical attention because of its elusive morphology and mysterious pathophysiology. However, a series of landmark discoveries made in the past decade has begun to change the previous misconception of the lymphatic system to be secondary to the more essential blood vascular system. In this article, we review the current understanding of the development and pathology of the lymphatic system. We hope to convince readers that the lymphatic system is no less essential than the blood circulatory system for human health and well-being.

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“…Nevertheless, recent work in the mouse shows that VEGF activates ERK signaling to induce expression of Dll4 and Hey via Foxc1/2, transcription factors (TFs) that directly bind to the Dll4 promoter (Hayashi and Kume, 2008;Seo et al, 2006). Furthermore, the amount of exogenous VEGF added to cultured endothelial cells greatly influences their differentiation into veins or arteries, with lower levels of VEGF favouring vein differentiation and higher levels inducing arterial specification (Lanner et al, 2007). This indicates that VEGF availability is a key factor during arterial specification.…”

Section: Hemogenic Endotheliummentioning

confidence: 99%

Genetic control of hematopoietic development in Xenopus and zebrafish

Ciau-Uitz¹,

Liu²,

Patient³

2010

Int. J. Dev. Biol.

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Blood development has been highly conserved during evolution. Hematopoietic cells in amphibian and fish embryos, as in mammalian embryos, emerge and progressively differentiate in several locations. Hematopoiesis, including of the immune system, is similar in the amphibian, Xenopus, to mammals and the embryos are ideal for tissue transplantation and lineage labelling experiments, which have enabled the elucidation of the distinct origins of embryonic and adult hematopoietic cells, as well as their migration pathways and organ colonisation behaviours. The zebrafish hematopoietic system is less well understood, but these embryos have recently emerged as a powerful system for both genetic analysis and imaging. In this review, we summarise our current knowledge of the cellular and genetic basis of ontogeny of the hematopoietic system in Xenopus and zebrafish embryos.

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Functional Arterial and Venous Fate Is Determined by Graded VEGF Signaling and Notch Status During Embryonic Stem Cell Differentiation

Cited by 86 publications

References 28 publications

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Genetic control of hematopoietic development in Xenopus and zebrafish

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