Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE–cadherin

M.I. Setyawati, C.Y. Tay, S.L. Chia, S.L. Goh, W. Fang, M.J. Neo, H.C. Chong, S.M. Tan, S.C.J. Loo, K.W. Ng, J.P. Xie, C.N. Ong, N.S. Tan and D.T. Leong ()
Additional contact information
M.I. Setyawati: National University of Singapore
C.Y. Tay: National University of Singapore
S.L. Chia: National University of Singapore
S.L. Goh: National University of Singapore
W. Fang: National University of Singapore
M.J. Neo: National University of Singapore
H.C. Chong: School of Biological Sciences, Nanyang Technological University
S.M. Tan: School of Biological Sciences, Nanyang Technological University
S.C.J. Loo: School of Materials Science and Engineering, Nanyang Technological University
K.W. Ng: School of Materials Science and Engineering, Nanyang Technological University
J.P. Xie: National University of Singapore
C.N. Ong: Saw Swee Hock School of Public Health, National University of Singapore
N.S. Tan: School of Biological Sciences, Nanyang Technological University
D.T. Leong: National University of Singapore

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract The use of nanomaterials has raised safety concerns, as their small size facilitates accumulation in and interaction with biological tissues. Here we show that exposure of endothelial cells to TiO2 nanomaterials causes endothelial cell leakiness. This effect is caused by the physical interaction between TiO2 nanomaterials and endothelial cells’ adherens junction protein VE-cadherin. As a result, VE-cadherin is phosphorylated at intracellular residues (Y658 and Y731), and the interaction between VE-cadherin and p120 as well as β-catenin is lost. The resulting signalling cascade promotes actin remodelling, as well as internalization and degradation of VE-cadherin. We show that injections of TiO2 nanomaterials cause leakiness of subcutaneous blood vessels in mice and, in a melanoma-lung metastasis mouse model, increase the number of pulmonary metastases. Our findings uncover a novel non-receptor-mediated mechanism by which nanomaterials trigger intracellular signalling cascades via specific interaction with VE-cadherin, resulting in nanomaterial-induced endothelial cell leakiness.

Date: 2013
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DOI: 10.1038/ncomms2655

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