Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion

Ubezio, Benedetta; Blanco, Raquel; Geudens, Ilse; Stanchi, Fabio; Mathivet, Thomas; Jones, Martin L.; Ragab, Anan; Bentley, Katie; Gerhardt, Holger

doi:10.7554/elife.12167

Cited by 114 publications

(148 citation statements)

References 46 publications

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“…The pathways that regulate the temporal VEGFdependent expression of DLL4 in tip cells are of particular importance considering the central role of this ligand, and its receptor, Notch, in directing tip and stalk cell behaviors (Hellström et al, 2007;Jakobsson et al, 2010;Suchting et al, 2007;Ubezio et al, 2016). Here, we identify one potential mechanism for the transient VEGFdependent induction of DLL4 transcription.…”

Section: Discussionmentioning

confidence: 94%

“…Dll4 is dynamically expressed in tip cells during sprouting angiogenesis (Hellström et al, 2007;Jakobsson et al, 2010;Suchting et al, 2007;Ubezio et al, 2016). We first delineated the kinetics of VEGF-dependent DLL4 transcription in vitro.…”

Section: Dynamic Mapk/erk Signaling Regulates Gene Induction In Respomentioning

confidence: 99%

“…Coordinating these dynamic cellular behaviors is essential for an effective angiogenic response. The molecular mechanisms responsible for the maintenance and conversion between these phenotypes are only partially understood, and include oscillations in DLL4 induction in the tip cell (Lobov et al, 2007;Ubezio et al, 2016), as well as tight control of Notch signal duration in neighboring stalk cells (Guarani et al, 2011). How VEGF-regulated transcriptional programs control the dynamic expression of DLL4 and other angiogenic genes during sprouting angiogenesis remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

et al. 2017

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The transcriptional pathways activated downstream of vascular endothelial growth factor (VEGF) signaling during angiogenesis remain incompletely characterized. By assessing the signals responsible for induction of the Notch ligand delta-like 4 (DLL4) in endothelial cells, we find that activation of the MAPK/ERK pathway mirrors the rapid and dynamic induction of DLL4 transcription and that this pathway is required for DLL4 expression. Furthermore, VEGF/ERK signaling induces phosphorylation and activation of the ETS transcription factor ERG, a prerequisite for DLL4 induction. Transcription of DLL4 coincides with dynamic ERG-dependent recruitment of the transcriptional co-activator p300. Genome-wide gene expression profiling identified a network of VEGF-responsive and ERG-dependent genes, and ERG chromatin immunoprecipitation (ChIP)-seq revealed the presence of conserved ERG-bound putative enhancer elements near these target genes. Functional experiments performed in vitro and in vivo confirm that this network of genes requires ERK, ERG and p300 activity. Finally, genome-editing and transgenic approaches demonstrate that a highly conserved ERG-bound enhancer located upstream of HLX (which encodes a transcription factor implicated in sprouting angiogenesis) is required for its VEGFmediated induction. Collectively, these findings elucidate a novel transcriptional pathway contributing to VEGF-dependent angiogenesis.

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Section: Discussionmentioning

confidence: 94%

Section: Dynamic Mapk/erk Signaling Regulates Gene Induction In Respomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

et al. 2017

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“…5B). Finely tuned regulation of the Notch pathway is required for vascular maturation (Pedrosa et al, 2015;Ubezio et al, 2016). In addition, expression of the main effector of the Notch pathway, Rbpj, in developing endothelial cells is required for vascular maturation in extra-embryonic tissues (Copeland et al, 2011).…”

Section: G9a Controls the Balance Of Endothelial And Trophoblast Prolmentioning

confidence: 99%

“…Evidence in vitro and in the mouse retina suggests that modulating the Notch pathway in endothelial cells favors vessel enlargement (Pedrosa et al, 2015;Ubezio et al, 2016). Notch signaling is required for vascular development and remodeling (Roca and Adams, 2007), and the main Notch effector, the transcription factor recombination signal binding protein for immunoglobulin kappa J (Rbpj), is required for extra-embryonic blood vessel maturation (Copeland et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Ehmt2/G9a controls placental vascular maturation by activating the Notch pathway

et al. 2017

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Defective fetoplacental vascular maturation causes intrauterine growth restriction (IUGR). A transcriptional switch initiates placental maturation where blood vessels elongate. However, cellular mechanisms and regulatory pathways involved are unknown. We show that the histone methyltransferase Ehmt2, also known as G9a, activates the Notch pathway to promote placental vascular maturation. Placental vasculature from embryos with G9a-deficient endothelial progenitor cells failed to expand due to decreased endothelial cell proliferation and increased trophoblast proliferation. Moreover, G9a deficiency altered the transcriptional switch initiating placental maturation and caused downregulation of Notch pathway effectors including Rbpj. Importantly, Notch pathway activation in G9a-deficient endothelial progenitors extended embryonic life and rescued placental vascular expansion. Thus, G9a activates the Notch pathway to balance endothelial cell and trophoblast proliferation and coordinates the transcriptional switch controlling placental vascular maturation. Accordingly, G9A and RBPJ were downregulated in human placentae from IUGR-affected pregnancies, suggesting that G9a is an important regulator in placental diseases caused by defective vascular maturation.

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Veins and Arteries Build Hierarchical Branching Patterns Differently: Bottom‐Up versus Top‐Down

Red‐Horse

Siekmann

2019

BioEssays

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A tree-like hierarchical branching structure is present in many biological systems, such as the kidney, lung, mammary gland, and blood vessels. Most of these organs form through branching morphogenesis, where outward growth results in smaller and smaller branches. However, the blood vasculature is unique in that it exists as two trees (arterial and venous) connected at their tips. Obtaining this organization might therefore require unique developmental mechanisms. As reviewed here, recent data indicate that arterial trees often form in reverse order. Accordingly, initial arterial endothelial cell differentiation occurs outside of arterial vessels. These pre-artery cells then build trees by following a migratory path from smaller into larger arteries, a process guided by the forces imparted by blood flow. Thus, in comparison to other branched organs, arteries can obtain their structure through inward growth and coalescence. Here, new information on the underlying mechanisms is discussed, and how defects can lead to pathologies, such as hypoplastic arteries and arteriovenous malformations.

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Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion

Cited by 114 publications

References 46 publications

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

Ehmt2/G9a controls placental vascular maturation by activating the Notch pathway

Veins and Arteries Build Hierarchical Branching Patterns Differently: Bottom‐Up versus Top‐Down

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