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VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

View Article: PubMed Central - PubMed

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 Vegfr2Y949F/Y949F leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2Y949F/Y949F mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2Y949F/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.

No MeSH data available.


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Schematic outline of Y949 signalling in VEGFA-regulated vascular permeability.WT and Vegfr2Y949F/Y949F (Y949F) endothelial junctions are shown (upper). In the WT, the junction is active, that is, VE-cadherin is not engaged in homophilic interaction, and VEGFA signalling results in c-Src activation at junctions. In the Y949F mutant, VEGFR2 remains in complex with VEPTP and VE-cadherin, promoting junctional quiescence. c-Src may be activated but not at junctions. Lower schematics shows that junctional activation in the WT results in extravasation of cells and molecules, causing tissue oedema as well as metastatic spread via tumour cell intravasation into the blood stream (cells indicated in green). In the Y949F mutant, extravasation and oedema are blocked and metastatic spread is suppressed, while inflammatory cell extravasation is unaffected.
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f7: Schematic outline of Y949 signalling in VEGFA-regulated vascular permeability.WT and Vegfr2Y949F/Y949F (Y949F) endothelial junctions are shown (upper). In the WT, the junction is active, that is, VE-cadherin is not engaged in homophilic interaction, and VEGFA signalling results in c-Src activation at junctions. In the Y949F mutant, VEGFR2 remains in complex with VEPTP and VE-cadherin, promoting junctional quiescence. c-Src may be activated but not at junctions. Lower schematics shows that junctional activation in the WT results in extravasation of cells and molecules, causing tissue oedema as well as metastatic spread via tumour cell intravasation into the blood stream (cells indicated in green). In the Y949F mutant, extravasation and oedema are blocked and metastatic spread is suppressed, while inflammatory cell extravasation is unaffected.

Mentions: We conclude that VEGFA-induced leakage (see Fig. 7 for a schematic outline of VEGFA signalling regulating vascular permeability/leakage) can be restricted during a window of time of B16F10 tumour growth, by suppressing the pY949 pathway. Moreover, the data indicate that VEGFA signalling is dynamically regulated by VEPTP in solid tumours.


VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
Schematic outline of Y949 signalling in VEGFA-regulated vascular permeability.WT and Vegfr2Y949F/Y949F (Y949F) endothelial junctions are shown (upper). In the WT, the junction is active, that is, VE-cadherin is not engaged in homophilic interaction, and VEGFA signalling results in c-Src activation at junctions. In the Y949F mutant, VEGFR2 remains in complex with VEPTP and VE-cadherin, promoting junctional quiescence. c-Src may be activated but not at junctions. Lower schematics shows that junctional activation in the WT results in extravasation of cells and molecules, causing tissue oedema as well as metastatic spread via tumour cell intravasation into the blood stream (cells indicated in green). In the Y949F mutant, extravasation and oedema are blocked and metastatic spread is suppressed, while inflammatory cell extravasation is unaffected.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4814575&req=5

f7: Schematic outline of Y949 signalling in VEGFA-regulated vascular permeability.WT and Vegfr2Y949F/Y949F (Y949F) endothelial junctions are shown (upper). In the WT, the junction is active, that is, VE-cadherin is not engaged in homophilic interaction, and VEGFA signalling results in c-Src activation at junctions. In the Y949F mutant, VEGFR2 remains in complex with VEPTP and VE-cadherin, promoting junctional quiescence. c-Src may be activated but not at junctions. Lower schematics shows that junctional activation in the WT results in extravasation of cells and molecules, causing tissue oedema as well as metastatic spread via tumour cell intravasation into the blood stream (cells indicated in green). In the Y949F mutant, extravasation and oedema are blocked and metastatic spread is suppressed, while inflammatory cell extravasation is unaffected.
Mentions: We conclude that VEGFA-induced leakage (see Fig. 7 for a schematic outline of VEGFA signalling regulating vascular permeability/leakage) can be restricted during a window of time of B16F10 tumour growth, by suppressing the pY949 pathway. Moreover, the data indicate that VEGFA signalling is dynamically regulated by VEPTP in solid tumours.

View Article: PubMed Central - PubMed

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 Vegfr2Y949F/Y949F leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2Y949F/Y949F mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2Y949F/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.

No MeSH data available.


Related in: MedlinePlus