title: Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress.
abstract: OBJECTIVE
  Mutations in the ALK1 gene, coding for an endothelial-specific receptor of the transforming growth factor-β superfamily, are the underlying cause of hereditary haemorrhagic telangiectasia type 2, but are also associated with familial pulmonary hypertension (PH). We assessed the lung vasculature of mice with a heterozygous deletion of Alk1 (Alk1(+/-)) for disease manifestations and levels of reactive O(2) species (ROS) implicated in both disorders.
  
  
  RESULTS
  Several signs of PH, including elevated right ventricular (RV) systolic pressure leading to RV hypertrophy, reduced vascular density, and increased thickness and outward remodelling of pulmonary arterioles, were observed in 8- to 18-week-old Alk1(+/-) mice relative to wild-type littermate controls. Higher ROS lung levels were also documented. At 3 weeks, Alk1(+/-) mice were indistinguishable from controls and were prevented from subsequently developing PH when treated with the anti-oxidant Tempol for 6 weeks, confirming a role for ROS in pathogenesis. Levels of NADPH oxidases and superoxide dismutases were higher in adults than newborns, but unchanged in Alk1(+/-) mice vs. controls. Prostaglandin metabolites were also normal in adult Alk1(+/-) lungs. In contrast, NO production was reduced, while endothelial NO synthase (eNOS)-dependent ROS production was increased in adult Alk1(+/-) mice. Pulmonary near resistance arteries from adult Alk1(+/-) mice showed less agonist-induced force and greater acetylcholine-induced relaxation; the later was normalized by catalase or Tempol treatment.
  
  
  CONCLUSIONS
  The increased pulmonary vascular remodelling in Alk1(+/-) mice leads to signs of PH and is associated with eNOS-dependent ROS production, which is preventable by anti-oxidant treatment.
authors.affiliation: Molecular Structure and Function Program,  Hospital for Sick Children, 555 University Ave., Toronto, ON,  Canada M5G 1X8.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Jerkic
authors.forename: Mohammed G
authors.initials: MG
authors.lastname: Kabir
authors.forename: Adrienne
authors.initials: A
authors.lastname: Davies
authors.forename: Lisa X
authors.initials: LX
authors.lastname: Yu
authors.forename: Brendan A S
authors.initials: BA
authors.lastname: McIntyre
authors.forename: Nasir W
authors.initials: NW
authors.lastname: Husain
authors.forename: Masahiro
authors.initials: M
authors.lastname: Enomoto
authors.forename: Valentin
authors.initials: V
authors.lastname: Sotov
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
authors.forename: Mark
authors.initials: M
authors.lastname: Henkelman
authors.forename: Jaques
authors.initials: J
authors.lastname: Belik
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
mesh_terms: D030201:Activin Receptors, Type I / Q000172:deficiency* / Q000235:genetics; D030301:Activin Receptors, Type II; D000367:Age Factors; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006579:Heterozygote; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000098:blood supply*; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
chemical_list: D000959:Antihypertensive Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D014665:Vasodilator Agents; D009569:Nitric Oxide; D002374:Catalase; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D011451:Prostaglandin-Endoperoxide Synthases; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; C001803:tempol