title: Enhanced Ca2+Entry and Tyrosine Phosphorylation Mediate Nanostructure-Induced Endothelial Proliferation.
abstract: Nanostructured substrates have been recognized to initiate transcriptional programs promoting cell proliferation. Specificallyβ-catenin has been identified as transcriptional regulator, activated by adhesion to nanostructures. We set out to identify processes responsible for nanostructure-induced endothelialβ-catenin signaling. Transmission electron microscopy (TEM) of cell contacts to differently sized polyethylene terephthalate (PET) surface structures (ripples with 250 to 300 nm and walls with 1.5 μm periodicity) revealed different patterns of cell-substrate interactions. Cell adhesion to ripples occurred exclusively on ripple peaks, while cells were attached to walls continuously. The Src kinase inhibitor PP2 was active only in cells grown on ripples, while the Abl inhibitors dasatinib and imatinib suppressedβ-catenin translocation on both structures. Moreover, Gd3+sensitive Ca2+entry was observed in response to mechanical stimulation or Ca2+store depletion exclusively in cells grown on ripples. Both PP2 and Gd3+suppressedβ-catenin nuclear translocation along with proliferation in cells grown on ripples but not on walls. Our results suggest that adhesion of endothelial cells to ripple structured PET induces highly specific, interface topology-dependent changes in cellular signalling, characterized by promotion of Gd3+-sensitive Ca2+entry and Src/Abl activation. We propose that these signaling events are crucially involved in nanostructure-induced promotion of cell proliferation.
authors.affiliation: Institute of Biophysics, Medical University Graz, 8010 Graz, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schernthaner
authors.affiliation: Department of Cell Biology, Histology and Embryology, Core Facility Ultrastructure Analysis, Center for Medical Research, Medical University Graz, 8010 Graz, Austria.
authors.forename: Gerd
authors.initials: G
authors.lastname: Leitinger
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Heimo
authors.initials: H
authors.lastname: Wolinski
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Sepp D
authors.initials: SD
authors.lastname: Kohlwein
authors.affiliation: Institute of Applied Physics, Johannes Kepler University Linz, 4040 Linz, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Reisinger
authors.affiliation: Institute of Applied Physics, Johannes Kepler University Linz, 4040 Linz, Austria.
authors.forename: Ruxandra-A
authors.initials: RA
authors.lastname: Barb
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University Graz, 8010 Graz, Austria.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
authors.affiliation: Institute of Applied Physics, Johannes Kepler University Linz, 4040 Linz, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Heitz
authors.affiliation: Institute of Biophysics, Medical University Graz, 8010 Graz, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Groschner
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