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

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.
- Received October 19, 2012.
- Accepted January 15, 2013.
- © 2013 American Heart Association, Inc.
Current Issue
Article Tools
- Organ-Specific Protection Against Lipopolysaccharide-Induced Vascular Leak Is Dependent on the Endothelial Protein C ReceptorAnnette von Drygalski, Christian Furlan-Freguia, Wolfram Ruf, John H. Griffin and Laurent O. MosnierArteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.112.301082, originally published February 7, 2013https://doi.org/10.1161/ATVBAHA.112.301082
Citation Manager Formats
Share this Article
- Organ-Specific Protection Against Lipopolysaccharide-Induced Vascular Leak Is Dependent on the Endothelial Protein C ReceptorAnnette von Drygalski, Christian Furlan-Freguia, Wolfram Ruf, John H. Griffin and Laurent O. MosnierArteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.112.301082, originally published February 7, 2013https://doi.org/10.1161/ATVBAHA.112.301082