title: Oxidative stress contributes to endothelial dysfunction in mouse models of hereditary hemorrhagic telangiectasia.
abstract: 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-β (TGF-β) 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 H(2)O(2) 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.
authors: Molecular Structure and Function Program, Hospital for Sick Children, Toronto, ON, Canada. mirjana.jerkic@sickkids.ca
authors: Mirjana
authors: M
authors: Jerkic
authors: Valentin
authors: V
authors: Sotov
authors: Michelle
authors: M
authors: Letarte
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II; D000818:Animals; D004195:Disease Models, Animal; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D009249:NADP; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; D019331:NG-Nitroarginine Methyl Ester