HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 290/3/R678    most recent 00246.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Ogunshola, O. O. Articles by Gassmann, M. Search for Related Content PubMed PubMed Citation Articles by Ogunshola, O. O. Articles by Gassmann, M.

GENETICALLY MODIFIED ANIMALS AND MODEL ORGANISMS

Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain

¹Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Centre for Integrative Human Physiology, University of Zürich, Zurich, Switzerland; ²Institute of Anatomy, University of Bern, Bern, Switzerland; and ³Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany

Submitted 8 April 2005 ; accepted in final form 21 October 2005

Excessive erythrocytosis results in severely increased blood viscosity, which may have significant detrimental effects on endothelial cells and, ultimately, function of the vascular endothelium. Because blood-brain barrier stability is crucial for normal physiological function, we used our previously characterized erythropoietin-overexpressing transgenic (tg6) mouse line (which has a hematocrit of 0.8–0.9) to investigate the effect of excessive erythrocytosis on vessel number, structure, and integrity in vivo. These mice have abnormally high levels of nitric oxide (NO), a potent proinflammatory molecule, suggesting altered vascular permeability and function. In this study, we observed that brain vessel density of tg6 mice was significantly reduced (16%) and vessel diameter was significantly increased (15%) compared with wild-type mice. Although no significant increases in vascular permeability under normoxic or acute hypoxic conditions (8% O₂ for 4 h) were detected, electron-microscopic analysis revealed altered morphological characteristics of the tg6 endothelium. Tg6 brain vascular endothelial cells appeared to be activated, with increased luminal protrusions reminiscent of ongoing inflammatory processes. Consistent with this observation, we detected increased levels of intercellular adhesion molecule-1 and von Willebrand factor, markers of endothelial activation and damage, in brain tissue. We propose that chronic excessive erythrocytosis and sustained high hematocrit cause endothelial damage, which may, ultimately, increase susceptibility to vascular disease.

erythropoietin; blood-brain barrier; vascular permeability

This article has been cited by other articles:

				K. Heinicke, O. Baum, O. O. Ogunshola, J. Vogel, T. Stallmach, D. P. Wolfer, S. Keller, K. Weber, P. D. Wagner, M. Gassmann, et al. Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R947 - R956. [Abstract] [Full Text] [PDF]