title: Thrombomodulin blocks calcineurin inhibitor-induced vascular permeability via inhibition of Src/VE-cadherin axis.
abstract: Recombinant human soluble thrombomodulin (rTM) counteracted capillary leakage and alleviated edema in individuals with sinusoidal obstruction syndrome and engraftment syndrome after hematopoietic stem cell transplantation. We previously showed that rTM increased levels of antiapoptotic protein Mcl-1 and protected endothelial cells from calcineurin inhibitor cyclosporine A (CsA)-induced apoptosis. However, the molecular mechanisms by which rTM enhances barrier function in vascular endothelial cells remain unknown. Here we show that exposure of vascular endothelial EA.hy926 cells to CsA induced phosphorylation of Src/vascular endothelial cadherin (VE-cadherin) and translocation of VE-cadherin from cell surface to cytoplasm, resulting in an increase in vascular permeability. In addition, CsA increased production of inflammatory cytokines, including interleukin (IL)-1β and IL-6, associated with an increase in nuclear levels of nuclear factor-κB (NF-κB) which also enhanced vascular permeability. Importantly, the fourth and fifth regions of epidermal growth factor-like domain of TM (TME45) attenuated CsA-induced p-Src/VE-cadherin and vascular permeability in parallel with a decrease in nuclear levels of NF-κB and cytokine production in EA.hy926 cells. In conclusion, TM, especially TME45, maintains vascular integrity, at least in part, via Src signaling.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan.|Department of Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ikezoe
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Nishioka
authors.affiliation: Department of Molecular Target Medicine Screening, School of Medicine, Aichi Medical University, Aichi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Umezawa
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D018180:Thrombomodulin / Q000008:administration & dosage*; D019061:src-Family Kinases / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D053583:Interleukin-1beta; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018180:Thrombomodulin; D019061:src-Family Kinases; D000099152:Cadherin 5; C587672:IL1B protein, mouse; C579094:Mcl1 protein, mouse; C546931:THBD protein, human; C577686:interleukin-6, mouse