title: Spontaneous adult-onset pulmonary arterial hypertension attributable to increased endothelial oxidative stress in a murine model of hereditary hemorrhagic telangiectasia.
abstract: OBJECTIVE
  Loss-of-function mutations in genes coding for transforming growth factor-beta/bone morphogenetic protein receptors and changes in nitric oxide(*) (NO(*)) bioavailability are associated with hereditary hemorrhagic telangiectasia and some forms of pulmonary arterial hypertension. How these abnormalities lead to seemingly disparate pulmonary pathologies remains unknown. Endoglin (Eng), a transforming growth factor-beta coreceptor, is mutated in hereditary hemorrhagic telangiectasia and involved in regulating endothelial NO(*) synthase (eNOS)-derived NO(*) production and oxidative stress. Because some patients with pulmonary arterial hypertension harbor ENG mutations leading to haplo insufficiency, we investigated the pulmonary vasculature of Eng(+/-) mice and the potential contribution of abnormal eNOS activation to pulmonary arterial hypertension.
  
  
  RESULTS
  Hemodynamic, histological, and biochemical assessments and x-ray micro-CT imaging of adult Eng(+/-) mice indicated signs of pulmonary arterial hypertension including increased right ventricular systolic pressure, degeneration of the distal pulmonary vasculature, and muscularization of small arteries. These findings were absent in 3-week-old Eng(+/-) mice and were attributable to constitutively uncoupled eNOS activity in the pulmonary circulation, as evidenced by reduced eNOS/heat shock protein 90 association and increased eNOS-derived superoxide ((*)O(2)(-)) production in a BH(4)-independent manner. These changes render eNOS unresponsive to regulation by transforming growth factor-beta/bone morphogenetic protein and underlie the signs of pulmonary arterial hypertension that were prevented by Tempol.
  
  
  CONCLUSIONS
  Adult Eng(+/-) mice acquire signs of pulmonary arterial hypertension that are attributable to uncoupled eNOS activity and increased (*)O(2)(-) production, which can be prevented by antioxidant treatment. Eng links transforming growth factor/bone morphogenetic protein receptors to the eNOS activation complex, and its reduction in the pulmonary vasculature leads to increased oxidative stress and pulmonary arterial hypertension.
authors.affiliation: Beth Israel Deaconess Medical Center, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Center for Vascular Biology Research, 99 Brookline Avenue, RN-233, Boston, MA 02115, USA. mtoporsi@bidmc.harvard.edu
authors.forename: Mourad
authors.initials: M
authors.lastname: Toporsian
authors.forename: Mirjana
authors.initials: M
authors.lastname: Jerkic
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhou
authors.forename: Mohammed G
authors.initials: MG
authors.lastname: Kabir
authors.forename: Lisa X
authors.initials: LX
authors.lastname: Yu
authors.forename: Brendan A S
authors.initials: BA
authors.lastname: McIntyre
authors.forename: Adrienne
authors.initials: A
authors.lastname: Davis
authors.forename: Yu Jing
authors.initials: YJ
authors.lastname: Wang
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Jaques
authors.initials: J
authors.lastname: Belik
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
authors.forename: Mark
authors.initials: M
authors.lastname: Henkelman
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000627:therapeutic use; D004195:Disease Models, Animal; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013113:Spin Labels; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D013113:Spin Labels; D016212:Transforming Growth Factor beta; D052250:Nitric Oxide Synthase Type III; D052004:Bone Morphogenetic Protein Receptors; C001803:tempol