title: Contribution of oxidative stress to endothelial dysfunction in hereditary hemorrhagic telangiectasia.
abstract: Oxidative stress causes endothelial dysfunction and is implicated in the pathogenesis of cardiovascular diseases. Our studies suggested that reactive oxygen species (ROS) play a crucial role in hereditary hemorrhagic telangiectasia (HHT) disease, a vascular dysplasia affecting 1 in 5,000-8,000 people. Mutations in endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) genes are responsible for HHT1 and HHT2 and are associated with arteriovenous malformations. ENG and ACVRL1 interact with endothelial nitric oxide synthase (eNOS) and regulate its activation. Mice heterozygous for these genes (Eng (+/-) and Acvrl1 (+/-)) show reduced ENG or ACVRL1 protein levels in endothelial cells causing eNOS uncoupling, generation of ROS rather than nitric oxide (NO•), leading to impaired NO• mediated vasodilation. ROS production is increased in several organs of Eng (+/-) and Acvrl1 (+/-) mice, including lungs, liver, and colon, affected in HHT. The major source of increased oxidative stress in these tissues is eNOS-derived ROS and not mitochondrial or NADPH oxidase-dependent ROS. Eng (+/-) and Acvrl1 (+/-) mice also develop with age signs of pulmonary arterial hypertension attributable to eNOS-derived ROS, which was preventable by antioxidant treatment. To date, only one pilot study has been carried out in HHT patients, and it showed beneficial effects of antioxidant therapy on epistaxis. We suggest that more clinical studies are warranted to investigate whether antioxidants would prevent, delay or attenuate manifestations of disease in individuals with HHT, based on our experimental data in mouse models.
authors.affiliation: Anesthesia Research, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto , Toronto, ON, Canada.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Jerkic
authors.affiliation: Molecular Structure and Function Program, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, University of Toronto , Toronto, ON, Canada ; Department of Immunology, University of Toronto , Toronto, ON, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
keywords: HHT; antioxidants; eNOS; nitric oxide; reactive oxygen species