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Oxidative Medicine and Cellular Longevity
Volume 2012 (2012), Article ID 686972, 9 pages
Research Article

Oxidative Stress Contributes to Endothelial Dysfunction in Mouse Models of Hereditary Hemorrhagic Telangiectasia

1Molecular Structure and Function Program, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8
2Heart and Stroke Richard Lewar Center of Excellence, University of Toronto, ON, Canada M5S 3E2
3Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8

Received 9 November 2012; Accepted 30 November 2012

Academic Editor: Sumitra Miriyala

Copyright © 2012 Mirjana Jerkic et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia caused by mutations in endoglin (ENG; HHT1) or activin receptor-like kinase (ALK1; HHT2) genes, coding for transforming growth factor- (TGF- ) superfamily receptors. We demonstrated previously that endoglin and ALK1 interact with endothelial NO synthase (eNOS) and affect its activation. Endothelial cells deficient in endoglin or ALK1 proteins show eNOS uncoupling, reduced NO, and increased reactive oxygen species (ROS) production. In this study, we measured NO and H2O2 levels in several organs of adult Eng and Alk1 heterozygous mice, to ascertain whether decreased NO and increased ROS production is a generalized manifestation of HHT. A significant reduction in NO and increase in ROS production were found in several organs, known to be affected in patients. ROS overproduction in mutant mice was attributed to eNOS, as it was L-NAME inhibitable. Mitochondrial ROS contribution, blocked by antimycin, was highest in liver while NADPH oxidase, inhibited by apocynin, was a major source of ROS in the other tissues. However, there was no difference in antimycin- and apocynin-inhibitable ROS production between mutant and control mice. Our results indicate that eNOS-derived ROS contributes to endothelial dysfunction and likely predisposes to disease manifestations in several organs of HHT patients.