Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression

Shawber, Carrie J.; Funahashi, Yasuhiro; Francisco, Esther; Vorontchikhina, Marina; Kitamura, Yoichi; Stowell, Stephanie A.; Borisenko, Valeriya; Feirt, Nikki; Podgrabinska, Simona; Shiraishi, Kazuko; Chawengsaksophak, Kallayanee; Rossant, Janet; Accili, Domenico; Skobe, Mihaela; Kitajewski, Jan

doi:10.1172/jci24311

Cited by 140 publications

(149 citation statements)

References 61 publications

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“…Activated Notch receptors on endothelial cells can in turn positively (VEGF-R1, VEGF-R3) [10][11][12] or negatively (VEGF-R2) [11] regulate the expression of VEGF receptors in those cells. Thus, Notch on endothelial cells can provide negative feedback to reduce VEGF activity.…”

Section: Discussionmentioning

confidence: 99%

“…This effect on angiogenesis probably occurs via several mechanisms. Most studies have suggested that Notch signaling can alter expression levels of all three VEGF receptors in cultured endothelial cells [10][11][12]. Although there is accumulating evidence that Notch signaling has an essential role in vascular development and angiogenesis, less is known about the function of Notch signaling in tumor angiogenesis [13,14].…”

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confidence: 99%

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Notch1 overexpression promotes cell growth and tumor angiogenesis in myeloma

Guo

C²,

Teng³

et al. 2012

neo

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Patients with multiple myeloma (MM) have increased bone marrow angiogenesis, but the angiogenic properties of myeloma cells and the mechanism of MM-induced angiogenesis have not been completely clarified. Notch1 signal has been identified as a critical factor in the regulation of vessel formation. However, the role of Notch1 in the angiogenesis of MM is unclear. We constitutively overexpressed active Notch1 in RPMI8226 cells to explore the effect of Notch1 signaling on cell growth and tumor angiogenesis in vivo and in vitro. We found that Notch1 overexpression promoted myeloma cells growth and increased drug resistance. Moreover, vascular endothelial growth factor (VEGF) expression was increased. Finally, our in vitro results were supported by the in vivo finding in human myeloma xenograft Nonobese diabetic/severe combined immunodeficient (NOD/SCID) models. Notch1 overexpression in MM cells resulted in up-regulation of VEGF expression, promotion of tumor growth, and increased microvessel density (MVD). Our study suggests that Notch1-induced angiogenesis is partly due to activation of VEGF pathway.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Notch1 overexpression promotes cell growth and tumor angiogenesis in myeloma

Guo

C²,

Teng³

et al. 2012

neo

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“…In fact, it has been proposed that the three endothelial cell fate regulators-namely, Notch (arterial) (Shawber et al 2007), COUP-TFII (venous) (You et al 2005), and Prox1 (lymphatic) -are all expressed in LECs and cross-regulate one another Kang et al 2010). 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 .…”

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

122

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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“…VEGFC/ VEGFR3 signaling activates Notch in blood vascular endothelial cells, facilitating the conversion of tip cells to stalk cells during the stabilization of vascular loops (16). Notch, in turn, regulates VEGFR3 expression in zebrafish and in postnatal mice (7,8,17).…”

mentioning

confidence: 99%

VEGFR3 does not sustain retinal angiogenesis without VEGFR2

Zarkada

Heinolainen

Mäkinen

et al. 2015

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

114

103

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Angiogenesis, the formation of new blood vessels, is regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). VEGFR2 is abundant in the tip cells of angiogenic sprouts, where VEGF/VEGFR2 functions upstream of the delta-like ligand 4 (DLL4)/Notch signal transduction pathway. VEGFR3 is expressed in all endothelia and is indispensable for angiogenesis during early embryonic development. In adults, VEGFR3 is expressed in angiogenic blood vessels and some fenestrated endothelia. VEGFR3 is abundant in endothelial tip cells, where it activates Notch signaling, facilitating the conversion of tip cells to stalk cells during the stabilization of vascular branches. Subsequently, Notch activation suppresses VEGFR3 expression in a negative feedback loop. Here we used conditional deletions and a Notch pathway inhibitor to investigate the cross-talk between VEGFR2, VEGFR3, and Notch in vivo. We show that postnatal angiogenesis requires VEGFR2 signaling also in the absence of Notch or VEGFR3, and that even small amounts of VEGFR2 are able to sustain angiogenesis to some extent. We found that VEGFR2 is required independently of VEGFR3 for endothelial DLL4 up-regulation and angiogenic sprouting, and for VEGFR3 functions in angiogenesis. In contrast, VEGFR2 deletion had no effect, whereas VEGFR3 was essential for postnatal lymphangiogenesis, and even for lymphatic vessel maintenance in adult skin. Knowledge of these interactions and the signaling functions of VEGFRs in blood vessels and lymphatic vessels is essential for the therapeutic manipulation of the vascular system, especially when considering multitargeted antiangiogenic treatments.

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Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression

Cited by 140 publications

References 61 publications

Notch1 overexpression promotes cell growth and tumor angiogenesis in myeloma

Notch1 overexpression promotes cell growth and tumor angiogenesis in myeloma

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

VEGFR3 does not sustain retinal angiogenesis without VEGFR2

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