期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms11017
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资金
- Swedish Cancer Society
- Swedish Science Council
- Knut and Alice Wallenberg Foundation
- Association for International Cancer Research/Worldwide Cancer Research [13-1295]
- Swiss National Science Foundation [31003A-130463]
- Oncosuisse grant [OC201200-08 -2007]
- European Research Council [294556 BBBARRIER]
- Leducq Foundation (Sphingonet)
- National Institute of Health [CA172983, CA175592]
- Wenner-Gren Foundation
- Swiss National Science Foundation (SNF) [31003A_130463] Funding Source: Swiss National Science Foundation (SNF)
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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