Beta3-integrin regulates vascular endothelial growth factor-A-dependent permeability.
OBJECTIVE
Beta3-integrin deficiency has been implicated in increasing levels of Flk-1 expression on endothelial cells and enhancing vascular endothelial growth factor (VEGF)-induced angiogenesis. We determined the role of beta3-integrin in mediating VEGF-A-induced blood vessel permeability through Flk-1.


RESULTS
Using the Miles assay, we demonstrated that VEGF-A-induced plasma leakage was enhanced in beta3-null mice when compared with wild-type controls. This was not caused by any changes in blood vessel structure (as detected by light or electron microscopy) or by changes in endothelial cell-cell adhesion proteins (as determined by Western blot analysis, flow cytometry, and immunofluorescence). Circulating levels of VEGF, baseline blood vessel leakage, and leakage in response to an acute inflammatory stimulus were identical in wild-type and beta3-null mice. However, VEGF-A-induced leakage was abolished in beta3-null mice by the inhibition of Flk-1, indicating that the elevated levels of Flk-1 on beta3-null endothelial cells enhance VEGF-A-induced permeability.


CONCLUSIONS
beta3-integrin-deficiency increases the sensitivity of endothelial cells to VEGF-A by elevating Flk-1 expression and, as a consequence, enhances VEGF-A-mediated permeability.
Robinson
Stephen D
SD
Cell Adhesion and Disease/Tumour Biology Laboratory, Cancer Research UK Clinical Centre, Queen Mary's School of Medicine & Dentistry at Barts & The London, John Vane Science Centre, London, United Kingdom. s.d.robinson@cancer.org.uk
Reynolds
Louise E
LE
Wyder
Lorenza
L
Hicklin
Daniel J
DJ
Hodivala-Dilke
Kairbaan M
KM
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000502:physiology; D002199:Capillary Permeability / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000502:physiology; D007249:Inflammation / Q000473:pathology; D039661:Integrin beta3 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000502:physiology
D039661:Integrin beta3; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2