title: Thioredoxin inhibits microvascular endothelial capillary tubule formation.
abstract: Thioredoxin (Trx) inhibited human HMEC-1 dermal microvascular endothelial cell capillary tubule forming capacity in a Matrigel based assay in vitro. Inhibition of capillary tubule formation was Trx catalytic site and thioredoxin reductase (TrxR) dependent, mediated at the Matrigel matrix level, and associated with a shift from morphological differentiation to continuous proliferation, with enhanced cell spreading resulting in eventual monolayer formation. Soluble complex carbohydrates, which inhibited capillary tubule formation on Matrigel without induction of cell spreading or monolayer formation, failed to impair Trx promotion of cell spreading and mono-layer formation, suggesting a shift away from carbohydrate-mediated cell/matrix adhesive interactions. Laminin peptides YIGRS and SIKVAV, which impaired tubule formation on Matrigel without inducing cell spreading or monolayer formation, partially impaired cell spreading upon Trx-treated Matrigel without restoring tubule formation, consistent with a potential role for laminin in Trx-mediated effects. Trx reduced laminin and destabilised laminin/galectin-3 complexes within Matrigel. Native purified EHS Laminin (also containing galectin-3), but not recombinant galectin-3, restored HMEC-1 capillary tubule formation on Trx-treated Matrigel. These data highlight a novel deregulatory effect of extracellular Trx upon morphological capillary differentiation that appears to depend upon the reduction of laminin and destabilisation of its interaction with galectin-3, possibly leading to galectin-3 neutralisation that shifts cell/matrix adhesive interactions away from being carbohydrate mediated and results in loss of proliferation-inhibiting and differentiation promoting cues from this tumor basement membrane matrix.
authors.affiliation: Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Antonietta R
authors.initials: AR
authors.lastname: Farina
authors.forename: Antonella
authors.initials: A
authors.lastname: Tacconelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Cappabianca
authors.forename: Giuseppina
authors.initials: G
authors.lastname: DeSantis
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Mackay
mesh_terms: D002196:Capillaries / Q000254:growth & development*; D002241:Carbohydrates / Q000494:pharmacology; D020134:Catalytic Domain; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D037502:Galectin 3 / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011509:Proteoglycans; D013880:Thioredoxin-Disulfide Reductase; D013879:Thioredoxins / Q000494:pharmacology*
chemical_list: D002241:Carbohydrates; D004338:Drug Combinations; D037502:Galectin 3; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D013879:Thioredoxins; D003094:Collagen; D013880:Thioredoxin-Disulfide Reductase