Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function

Williams, Cheyenne; Li, Jiliang; Murga, Matilde; Harris, Adrian L.; Tosato, Giovanna

doi:10.1182/blood-2005-03-1000

Cited by 325 publications

(333 citation statements)

References 65 publications

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“…Dll-4-induced Notch activation in ECs was recently shown to down-regulate EC proliferation, maybe due to an attenuated responsiveness to VEGF. 54 However, despite this inhibitory effect on EC proliferation, Notch activation was still compatible with up-regulation of arterial EC markers, such as Hey-2, similar to what we and others documented in in vitro studies. 55,56 Shh has also been shown to support neuronal differentiation, 57 yet we did not observe the formation of neurons in our system despite the intrinsic ability of hMAPCs for neuronal differentiation, the latter of which requires a different cytokine cocktail ( Figure S1; Document S1).…”

Section: Discussionsupporting

confidence: 86%

In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

Aranguren

Luttun

Clavel

et al. 2006

Blood

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IntroductionThe vascular system is a bipolar complex network of arteries that transport oxygen-rich blood to all tissues and veins that bring oxygendeprived blood back to the heart. 1 Because of this bipolar set-up, arteries and veins feature anatomic and physiological differences. Unlike venous endothelium, arterial endothelium is surrounded by several layers of smooth muscle cells (SMCs), separated by elastic laminae, and embedded in a thick layer of fibrillar collagen. 2 Moreover, both vessel types have a differential susceptibility to atherosclerotic disease, possibly due to exposure to different levels of shear stress. Arterial and venous endothelial cells (ECs) also have a distinct molecular signature, and such molecular specification occurs before the onset of blood flow. 3 Indeed, arteriovenous (AV) specification of ECs is accomplished early in development and is associated with the expression of a specific complement of factors: venous endothelium is characterized by the expression of EphB4, 4 Lefty-1, 5 Lefty-2, 5 COUP-TFII, 6 and MYO1-␤, 5 and arterial ECs express high levels of Notch 1 and 4, 7 Dll-4, 8 EphrinB1 and EphrinB2, 4 Jagged-1 and -2, 7 connexin-40, and Hey-2 (gridlock zebrafish ortholog). 9,10 Studies in Xenopus, zebrafish, and mice have revealed that, besides blood flow, 11 vessel-intrinsic cues and-later in development-signals from outside the vasculature 12,13 are implicated in defining arterial or venous fate such as members of the TGF-␤ pathway, 14,15 VEGF isoforms,13,[16][17][18]17 angiopoietins, 19 the Notch pathway, 7,9,20-22 the patched pathway, 20 and COUP-TFII, a member of the orphan nuclear receptor superfamily. 6 Although it has been shown that some of these pathways are well conserved from zebrafish to mouse, less information is available on whether they have a similar role in humans. Because these molecular differences between arterial and venous ECs exist independently of blood flow and some of these factors work in an EC-intrinsic way, 2 it should be possible to manipulate some or all of these to endow ECs with an arterial or venous fate. Consistent with this notion, recent studies have suggested that arterial markers can be induced in primary mature ECs. 5,13,21,23,24 Many different stem cell populations, including bone marrow (BM) mononuclear cells, AC133 ϩ endothelial progenitor cells, and embryonic stem cells have the potential to differentiate in vitro and in vivo into mature and functional ECs. 4,[25][26][27][28] We have recently described another stem cell population, multipotent adult progenitor cells (MAPCs), that differentiates into most somatic cell types, including functional ECs, in vitro and in vivo. [29][30][31][32][33] The question of whether and how these stem cells can be coaxed into arterial or venous ECs has thus far not been addressed. In this study, we analyzed the in vitro and in vivo arterial and venous endothelial differentiation of human MAPCs (hMAPCs) and hAC133 ϩ cells. Materials and methodsAdditional and extended descriptions of methods are inc...

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Section: Discussionsupporting

confidence: 86%

In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

Aranguren

Luttun

Clavel

et al. 2006

Blood

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“…In contrast to vessel in-growth models as in (Anderson and Chaplain, 1998) tip-cells are not dominantly generated by branching of existing tip-cells but by sprouting from vessels of the original network. This tip-cell generation from existing vessels is initiated by activation of VEGF receptors with subsequent up-regulation of the delta-like-4 (Dll4) ligand in one EC (Liu et al, 2003), and the Dll4-mediated activation of Notch1 receptors in the neighbouring EC (Sainson et al, 2005;Williams et al, 2006). This lateral inhibition leads to an alternating pattern of cell fates in capillary walls under the influence of VEGF and results in a separation of one to two non-tip-cells between each tip cell.…”

Section: Sprouting Angiogenesismentioning

confidence: 99%

Vascular remodelling of an arterio-venous blood vessel network during solid tumour growth

Welter

Bartha

Rieger

2009

Journal of Theoretical Biology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d m a n u s c r i p t AbstractWe formulate a theoretical model to analyse the vascular remodelling process of an arterio-venous vessel network during solid tumour growth. The model incorporates a hierarchically organized initial vasculature comprising arteries, veins and capillaries, and involves sprouting angiogenesis, vessel cooption, dilation and regression as well as tumour cell proliferation and death. The emerging tumour vasculature is non-hierarchical, compartmentalized into well characterized zones and transports efficiently an injected drug-bolus. It displays a complex geometry with necrotic zones and "hot spots" of increased vascular density and blood flow of varying size. The corresponding cluster size distribution is algebraic, reminiscent of a self-organized critical state.The intra-tumour vascular-density fluctuations correlate with pressure drops in the initial vasculature suggesting a physical mechanism underlying hot-spot formation.

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“…Retroviruses were packaged in the Phoenix packaging cell line, as described. 28 Two-day culture supernatants were filtered, supplemented with Polybrene (4 mg/mL, final concentration; SigmaAldrich) and used for infection. Two days after infection with Gfi1-GFP-RV and GFP-RV retroviruses, GFP-expressing 32D cells were sorted; only cell populations at least 80% GFP ϩ were used for experiments.…”

Section: Retroviral Constructs Infection and Small Interfering Rnamentioning

confidence: 99%

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

Sierra

Sakakibara

Gasperini

et al. 2010

Blood

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The transcription factor growth factor independence 1 (Gfi1) and the growth factor granulocyte colony-stimulating factor (G-CSF) are individually essential for neutrophil differentiation from myeloid progenitors. Here, we provide evidence that the functions of Gfi1 and G-CSF are linked in the regulation of granulopoiesis. We report that Gfi1 promotes the expression of Ras guanine nucleotide releasing protein 1 (RasGRP1), an exchange factor that activates Ras, and that RasGRP1 is required for G-CSF signaling through the Ras/ mitogen-activated protein/extracellular signal-regulated kinase (MEK/Erk) pathway. Gfi1-null mice have reduced levels of RasGRP1 mRNA and protein in thymus, spleen, and bone marrow, and Gfi1 transduction in myeloid cells promotes RasGRP1 expression. When stimulated with G-CSF, Gfi1-null myeloid cells are selectively defective at activating Erk1/2, but not signal transducer and activator of transcription 1 (STAT1) or STAT3, and fail to differentiate into neutrophils. Expression of RasGRP1 in Gfi1-deficient cells rescues Erk1/2 activation by G-CSF and allows neutrophil maturation by G-CSF. These results uncover a previously unknown function of Gfi1 as a regulator of RasGRP1 and link Gfi1 transcriptional control to G-CSF signaling and regulation of granulopoiesis

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Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function

Cited by 325 publications

References 65 publications

In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

Vascular remodelling of an arterio-venous blood vessel network during solid tumour growth

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

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