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Vascular Biology

Organ-Specific Protection Against Lipopolysaccharide-Induced Vascular Leak Is Dependent on the Endothelial Protein C Receptor

Annette von Drygalski, Christian Furlan-Freguia, Wolfram Ruf, John H. Griffin, Laurent O. Mosnier
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https://doi.org/10.1161/ATVBAHA.112.301082
Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.112.301082
Originally published February 7, 2013
Annette von Drygalski
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (A.V.D., J.H.G., L.O.M.); Department of Medicine, University of California San Diego, San Diego, CA (A.V.D., J.H.G.); and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (C.F.-F., W.R.).
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Christian Furlan-Freguia
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (A.V.D., J.H.G., L.O.M.); Department of Medicine, University of California San Diego, San Diego, CA (A.V.D., J.H.G.); and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (C.F.-F., W.R.).
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Wolfram Ruf
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (A.V.D., J.H.G., L.O.M.); Department of Medicine, University of California San Diego, San Diego, CA (A.V.D., J.H.G.); and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (C.F.-F., W.R.).
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John H. Griffin
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (A.V.D., J.H.G., L.O.M.); Department of Medicine, University of California San Diego, San Diego, CA (A.V.D., J.H.G.); and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (C.F.-F., W.R.).
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Laurent O. Mosnier
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (A.V.D., J.H.G., L.O.M.); Department of Medicine, University of California San Diego, San Diego, CA (A.V.D., J.H.G.); and Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (C.F.-F., W.R.).
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Abstract

Objective—To study the role of the endothelial protein C receptor (EPCR) in the modulation of susceptibility to inflammation-induced vascular leak in vivo.

Approach and Results—Genetically modified mice with low, <10% EPCR expression (EPCRlow) and control mice were challenged with lipopolysaccharides in a mouse model of endotoxemia. Infrared fluorescence and quantification of albumin-bound Evans Blue in tissues and intravascular plasma volumes were used to assess plasma extravasation. Pair-wise analysis of EPCRlow and control mice matched for sex, age, and weight allowed determination of EPCR-dependent vascular leak. Kidney, lung, and brain were the organs with highest discriminative increased Evans Blue accumulation in EPCRlow versus control mice in response to lipopolysaccharides. Histology of kidney and lung confirmed the EPCR-specific pathology. In addition to severe kidney injury in response to lipopolysaccharides, EPCRlow and anti-EPCR–treated wild-type mice suffered from enhanced albuminuria and profound renal hemorrhage versus controls. Intravascular volume loss at the same extent of weight loss in EPCRlow mice compared with control mice provided proof that plasma leak was the predominant cause of Evans Blue tissue accumulation.

Conclusions—This study demonstrates an important protective role for EPCR in vivo against vascular leakage during inflammation and suggests that EPCR-dependent vascular protection is organ-specific.

  • endothelial protein C receptor
  • endothelium
  • endotoxemia
  • inflammation
  • vascular leak
  • Received October 19, 2012.
  • Accepted January 15, 2013.
  • © 2013 American Heart Association, Inc.
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    Organ-Specific Protection Against Lipopolysaccharide-Induced Vascular Leak Is Dependent on the Endothelial Protein C Receptor
    Annette von Drygalski, Christian Furlan-Freguia, Wolfram Ruf, John H. Griffin and Laurent O. Mosnier
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.112.301082, originally published February 7, 2013
    https://doi.org/10.1161/ATVBAHA.112.301082

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    Organ-Specific Protection Against Lipopolysaccharide-Induced Vascular Leak Is Dependent on the Endothelial Protein C Receptor
    Annette von Drygalski, Christian Furlan-Freguia, Wolfram Ruf, John H. Griffin and Laurent O. Mosnier
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.112.301082, originally published February 7, 2013
    https://doi.org/10.1161/ATVBAHA.112.301082
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