title: Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE-cadherin.
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.
authors.affiliation: Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117576, Singapore.
authors.forename: M I
authors.initials: MI
authors.lastname: Setyawati
authors.forename: C Y
authors.initials: CY
authors.lastname: Tay
authors.forename: S L
authors.initials: SL
authors.lastname: Chia
authors.forename: S L
authors.initials: SL
authors.lastname: Goh
authors.forename: W
authors.initials: W
authors.lastname: Fang
authors.forename: M J
authors.initials: MJ
authors.lastname: Neo
authors.forename: H C
authors.initials: HC
authors.lastname: Chong
authors.forename: S M
authors.initials: SM
authors.lastname: Tan
authors.forename: S C J
authors.initials: SC
authors.lastname: Loo
authors.forename: K W
authors.initials: KW
authors.lastname: Ng
authors.forename: J P
authors.initials: JP
authors.lastname: Xie
authors.forename: C N
authors.initials: CN
authors.lastname: Ong
authors.forename: N S
authors.initials: NS
authors.lastname: Tan
authors.forename: D T
authors.initials: DT
authors.lastname: Leong
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D049329:Nanostructures; D018384:Oxidative Stress; D014025:Titanium / Q000494:pharmacology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D014025:Titanium; D000099152:Cadherin 5; C009495:titanium dioxide