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A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
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A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors

Published on: March 15, 2016

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Myc-dependent endothelial proliferation is controlled by phosphotyrosine 1212 in VEGF receptor-2

Chiara Testini1, Ross O Smith1, Yi Jin1

  • 1Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

EMBO Reports
|September 24, 2019
PubMed

Insights

Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Y1212 signaling is crucial for endothelial cell proliferation and vessel stability. Targeting this specific pathway offers new therapeutic strategies for vascular diseases.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Vascular Biology

Background:

  • Vascular Endothelial Growth Factor (VEGF)-A and its receptor, VEGFR2, signaling are critical for blood vessel formation and function.
  • Dysregulated VEGFR2 signaling contributes to various pathologies, but its complete suppression can worsen disease.
  • Understanding specific VEGFR2 signaling pathways is essential for developing targeted therapeutic strategies.

Purpose of the Study:

  • To investigate the role of the VEGFR2 Y1212 tyrosine residue in downstream signaling pathways.
  • To determine the impact of VEGFR2 Y1212 signaling on endothelial cell proliferation and embryonic development in vivo.
  • To explore potential rescue mechanisms for impaired VEGFR2 signaling.

Main Methods:

  • Generation of knock-in mouse models (VEGFR2 Y1212F) in C57Bl/6 and FVB strains.
  • Analysis of downstream signaling pathways, including growth factor receptor-bound protein 2 (Grb2) and phosphoinositide 3'-kinase (PI3K)p85.
  • Assessment of embryonic and postnatal endothelial cell (EC) proliferation and survival.
  • Rescue experiments involving c-Myc overexpression in EC explants.

Main Results:

  • VEGFR2 Y1212F mutation abrogated Grb2 and PI3K signaling.
  • C57Bl/6 Vegfr2Y1212F/Y1212F mice exhibited reduced embryonic EC proliferation and partial lethality.
  • FVB Vegfr2Y1212F/Y1212F mice displayed reduced postnatal EC proliferation.
  • c-Myc overexpression rescued EC proliferation in Vegfr2Y1212F/Y1212F explants.

Conclusions:

  • VEGFR2 Y1212 signaling activates extracellular-signal-regulated kinase (ERK)1/2 and Akt pathways.
  • These pathways are essential for c-Myc-dependent gene regulation, driving endothelial cell proliferation.
  • Targeting VEGFR2 Y1212 signaling offers a precise approach to modulate EC function and vessel stability in disease contexts.
Keywords:
GRB2NckPI3Kp85angiogenesisproliferation

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