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VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

Li, Xiujuan; Padhan, Narendra; Sjöström, Elisabet O; Roche, Francis P; Testini, Chiara; Honkura, Naoki; Sáinz-Jaspeado, Miguel; Gordon, Emma; Bentley, Katie and Philippides, Andrew, et al. (2016) In Nature Communications 7.
Abstract

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly,... (More)

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

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published
subject
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Nature Communications
volume
7
publisher
Nature Publishing Group
external identifiers
  • WOS:000372721400001
  • Scopus:84962295137
ISSN
2041-1723
DOI
10.1038/ncomms11017
language
English
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yes
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c2e400ca-9245-4b48-ab14-9182ab341a61
date added to LUP
2016-04-12 12:42:10
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2016-10-13 05:06:02
@misc{c2e400ca-9245-4b48-ab14-9182ab341a61,
  abstract     = {<p>The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.</p>},
  author       = {Li, Xiujuan and Padhan, Narendra and Sjöström, Elisabet O and Roche, Francis P and Testini, Chiara and Honkura, Naoki and Sáinz-Jaspeado, Miguel and Gordon, Emma and Bentley, Katie and Philippides, Andrew and Tolmachev, Vladimir and Dejana, Elisabetta and Stan, Radu V and Vestweber, Dietmar and Ballmer-Hofer, Kurt and Betsholtz, Christer and Pietras, Kristian and Jansson, Leif and Claesson-Welsh, Lena},
  issn         = {2041-1723},
  language     = {eng},
  month        = {02},
  publisher    = {ARRAY(0xbd96cd8)},
  series       = {Nature Communications},
  title        = {VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread},
  url          = {http://dx.doi.org/10.1038/ncomms11017},
  volume       = {7},
  year         = {2016},
}