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Research Article Free access | 10.1172/JCI114540

Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium. Increased monolayer permeability and induction of procoagulant properties.

S Ogawa, H Gerlach, C Esposito, A Pasagian-Macaulay, J Brett, and D Stern

Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York 10032.

Find articles by Ogawa, S. in: PubMed | Google Scholar

Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York 10032.

Find articles by Gerlach, H. in: PubMed | Google Scholar

Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York 10032.

Find articles by Esposito, C. in: PubMed | Google Scholar

Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York 10032.

Find articles by Pasagian-Macaulay, A. in: PubMed | Google Scholar

Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York 10032.

Find articles by Brett, J. in: PubMed | Google Scholar

Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York 10032.

Find articles by Stern, D. in: PubMed | Google Scholar

Published April 1, 1990 - More info

Published in Volume 85, Issue 4 on April 1, 1990
J Clin Invest. 1990;85(4):1090–1098. https://doi.org/10.1172/JCI114540.
© 1990 The American Society for Clinical Investigation
Published April 1, 1990 - Version history
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Abstract

Exposure of cultured endothelium to environments with low concentrations of oxygen, in the range of those observed in pathophysiologic hypoxemic states in vivo, compromises cellular barrier and coagulant function. An atmosphere with PO2 approximately 14 mm Hg was not lethally toxic to endothelial cultures, but cells became larger and exhibited small intercellular gaps. At low oxygen concentrations, passage of macromolecular tracers through hypoxic endothelial monolayers was accelerated in a time- and dose-dependent manner, presumably by a paracellular pathway via the gaps. Cell surface coagulant properties of the endothelium were also perturbed. At PO2 approximately 14 mm Hg thrombomodulin antigen and functional activity on the cell surface were diminished by 80-90%, and Northern blots demonstrated suppression of thrombomodulin mRNA. The decrease in thrombomodulin was twice as great compared with the general decline in total protein synthesis in hypoxia. In addition, expression of a direct Factor X activator developed under hypoxic conditions; the activator was membrane-associated and expressed on the surface of intact cultures, Ca-dependent, inhibited by HgCl2 but not PMSF, and had Km approximately 25 micrograms/ml for the substrate at pH 7.4. Synthesis of the activator was blocked by inclusion of cycloheximide, but not warfarin, in the culture medium. These results demonstrate that endothelial function is perturbed in a selective manner in the presence of low concentrations of oxygen, providing insights into mechanisms which may contribute to vascular dysfunction in hypoxemic states.

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