title: Hypobaric hypoxia down-regulated junctional protein complex: Implications to vascular leakage.
abstract: Acute mountain sickness (AMS) can cause capillary hyper-permeability and vasogenic edema. However, its underlying mechanisms remained unclear and there is no previous in vitro study on AMS. We therefore conducted an in vitro study and examined whether continuous hypobaric hypoxia (CHH) could alter expression of junctional protein complex of vascular endothelial cells, causing hyper-permeabilization. EA.hy926 human endothelial cells were exposed to either CHH or normoxia for up to 24 h. Flow cytometry using annexin V/propidium iodide co-staining demonstrated that cell death had no significant difference at 12-h, but was increased by CHH at 24-h. Transendothelial resistance (TER) of endothelial cell monolayer was progressively decreased by CHH from 1-h to 24-h. Western blot analysis and immunofluorescence study demonstrated decreased expression levels of VE-cadherin, PECAM-1 and ZO-1 junctional proteins at both 12-h and 24-h exposure time-points. Interestingly, while the main form of ZO-1 (220 kDa) was decreased, its degraded form (100 kDa) was increased by 24-h CHH that might be linked to the increased cell death. Our data have demonstrated that CHH caused vascular endothelial hyper-permeability and defective junctional protein complex by reducing expression levels of VE-cadherin, PECAM-1, and ZO-1. Taken together, these data may explain pathophysiology underlying vascular hyper-permeability in AMS.
authors.affiliation: a Department of Physiology , Phramongkutklao College of Medicine , Bangkok , Thailand.
authors.forename: Dangjai
authors.initials: D
authors.lastname: Souvannakitti
authors.affiliation: b Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University , Bangkok , Thailand.|c Center for Research in Complex Systems Science (CRCSS), Mahidol University , Bangkok , Thailand.
authors.forename: Paleerath
authors.initials: P
authors.lastname: Peerapen
authors.affiliation: b Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University , Bangkok , Thailand.|c Center for Research in Complex Systems Science (CRCSS), Mahidol University , Bangkok , Thailand.
authors.forename: Visith
authors.initials: V
authors.lastname: Thongboonkerd
mesh_terms: D001808:Blood Vessels / Q000378:metabolism* / Q000473:pathology*; D002199:Capillary Permeability; D016923:Cell Death; D002460:Cell Line; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007365:Intercellular Junctions / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins
keywords: PECAM; VE-cadherin; ZO-1; adhesion molecule; endothelial cell; hypobaric hypoxia; permeability; vascular leakage