title: T-cadherin modulates endothelial barrier function.
abstract: T-cadherin is an atypical member of the cadherin family, which lacks the transmembrane and intracellular domains and is attached to the plasma membrane via a glycosylphosphatidylinositol anchor. Unlike canonical cadherins, it is believed to function primarily as a signaling molecule. T-cadherin is highly expressed in endothelium. Using transendothelial electrical resistance measurements and siRNA-mediated depletion of T-cadherin in human umbilical vein endothelial cells, we examined its involvement in regulation of endothelial barrier. We found that in resting confluent monolayers adjusted either to 1% or 10% serum, T-cadherin depletion modestly, but consistently reduced transendothelial resistance. This was accompanied by increased phosphorylation of Akt and LIM kinase, reduced phosphorylation of p38 MAP kinase, but no difference in tubulin acetylation and in phosphorylation of an actin filament severing protein cofilin and myosin light chain kinase. Serum stimulation elicited a biphasic increase in resistance with peaks at 0.5 and 4-5 h, which was suppressed by a PI3 kinase/Akt inhibitor wortmannin and a p38 inhibitor SB 239063. T-cadherin depletion increased transendothelial resistance between the two peaks and reduced the amplitude of the second peak. T-cadherin depletion abrogated serum-induced Akt phosphorylation at Thr308 and reduced phosphorylation at Ser473, reduced phosphorylation of cofilin, and accelerated tubulin deacetylation. Adiponectin slightly improved transendothelial resistance irrespectively of T-cadherin depletion. T-cadherin depletion also resulted in a reduced sensitivity and delayed responses to thrombin. These data implicate T-cadherin in regulation of endothelial barrier function, and suggest a complex signaling network that links T-cadherin and regulation of barrier function.
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois 60612, USA. aandreev@uic.edu
authors.forename: Alexandra V
authors.initials: AV
authors.lastname: Andreeva
authors.forename: Jingyan
authors.initials: J
authors.lastname: Han
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kutuzov
authors.forename: Jasmina
authors.initials: J
authors.lastname: Profirovic
authors.forename: Vsevolod A
authors.initials: VA
authors.lastname: Tkachuk
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Voyno-Yasenetskaya
mesh_terms: D000107:Acetylation; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D024722:Cardiac Myosins / Q000378:metabolism; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C499918:ADIPOQ protein, human; D051339:Actin Depolymerizing Factors; D052242:Adiponectin; D015820:Cadherins; C099972:H-cadherin; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D014404:Tubulin; C107184:myosin light chain 2; D054461:Lim Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D024722:Cardiac Myosins