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Cited by 76Angiogenesis and VEGF in CancerDevelopmental Biology and Gene RegulationZebrafish Biomedical Research Applications

Vegf signaling promotes vascular endothelial differentiation by modulating etv2 expression

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Casie Chetty, Satish, Rost, Megan S., Enriquez, Jacob Ryan, Schumacher, Jennifer A., Baltrunaite, Kristina, Rossi, Andrea, Stainier, Didier Y.R., Sumanas, Saulius·2017·Developmental Biology
DOI 10.1016/j.ydbio.2017.03.005PMC PMC5419721
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Abstract

Vasculogenesis involves the differentiation of vascular endothelial progenitors de novo from undifferentiated mesoderm, their migration and coalescence to form the major embryonic vessels and the acquisition of arterial or venous identity. Vascular Endothelial Growth Factor (Vegf) signaling plays multiple roles during vascular development. However, its function during embryonic vasculogenesis has been controversial. Previous studies have implicated Vegf signaling in either regulating arteriovenous specification or overall vascular endothelial differentiation. To clarify the role of Vegf in embryonic vasculogenesis and identify its downstream targets, we used chemical inhibitors of Vegf receptor (Vegfr) signaling in zebrafish embryos as well as zebrafish genetic mutants. A high level of chemical inhibition of Vegfr signaling resulted in the reduction of overall vascular endothelial marker gene expression, including downregulation of both arterial and venous markers, ultimately leading to the apoptosis of vascular endothelial cells. In contrast, a low level of Vegfr inhibition specifically blocked arterial specification while the expression of venous markers appeared largely unaffected or increased. Inhibition of Vegfr signaling prior to the initiation of vasculogenesis reduced overall vascular endothelial differentiation, while inhibition of Vegfr signaling starting at mid-somitogenesis stages largely inhibited arterial specification. Conversely, Vegf overexpression resulted in the expansion of both arterial and pan-endothelial markers, while the expression of several venous-specific markers was downregulated. We further show that Vegf signaling affects overall endothelial differentiation by modulating the expression of the ETS transcription factor etv2/ etsrp. etv2 expression was downregulated in Vegfr- inhibited embryos, and expanded in Vegfaa-overexpressing embryos. Furthermore, vascular-specific overexpression of etv2 in Vegfr-inhibited embryos rescued defects in vascular endothelial differentiation. Similarly, vegfaa genetic mutants displayed a combination of the two phenotypes observed with chemical Vegfr inhibition: the expression of arterial and pan-endothelial markers including etv2 was downregulated while the expression of most venous markers was either expanded or unchanged. Based on these results we propose a revised model which explains the different phenotypes observed upon inhibition of Vegf signaling: low levels of Vegf signaling promote overall vascular endothelial differentiation and cell survival by upregulating etv2 expression, while high levels of Vegf signaling promote arterial and inhibit venous specification.

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  • Endothelial differentiation was evaluated with observation of DLL4+ arterial capillaries and EMCN+ venous capillaries, highlighting appropriate recapitulation of a blood vessel as seen in vivo.

    “Additionally, endothelial differentiation was evaluated with an observation of DLL4+ arterial capillaries and EMCN+ venous capillaries, highlighting the appropriate recapitulation of a blood vessel as seen in vivo.[ 74 , 75 ]”

    From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [74]

    Results §3.1 examines arterial and venous marker expression during endothelial differentiation in zebrafish embryos. It does not report DLL4+ arterial or EMCN+ venous capillaries, or evaluate whether a vessel recapitulates one seen in vivo; those specific parts of the claim are unsupported. (LLM, conf=0.83)

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Authors
Casie Chetty, S., Rost, M. S., Enriquez, J. R., Schumacher, J. A., Baltrunaite, K., Rossi, A., Stainier, D. Y. R., & Sumanas, S.
Affiliations
  • Cincinnati Children's Hospital Medical Center (US)
  • Max Planck Institute for Heart and Lung Research (DE)
Corresponding author
Sumanas, Saulius
ORCID
Venue
Developmental Biology
Publisher
Elsevier BV
Published
2017-04
Volume
424
Issue
2
Pages
147-161
ISSN
0012-1606 (ISSN-L)
DOI
10.1016/j.ydbio.2017.03.005
PMC
PMC5419721
OpenAlex
W2592373733
Cited by
76
References
0
Citations by year
2026: 12 · 2025: 13 · 2024: 10 · 2023: 9 · 2022: 10 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 1
FWCI
1.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL107369)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
Keywords
VEGF signaling, ETV2, ETS transcription factors, vasculogenesis, arterial specification, endothelial cell apoptosis, zebrafish embryos
MeSH terms
Animals, Arteries, Cell Count, Cell Differentiation, Embryo, Nonmammalian, Indoles, Models, Biological, Mutation, Pyrroles, Veins, Zebrafish, Signal Transduction, Biomarkers, Gene Expression Regulation, Developmental, Somites, Zebrafish Proteins, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A, Endothelial Cells, Gene Knockdown Techniques, Morpholinos

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