| First Author | Jerkic M | Year | 2011 |
| Journal | Cardiovasc Res | Volume | 92 |
| Issue | 3 | Pages | 375-84 |
| PubMed ID | 21859819 | Mgi Jnum | J:191704 |
| Mgi Id | MGI:5462331 | Doi | 10.1093/cvr/cvr232 |
| Citation | Jerkic M, et al. (2011) Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress. Cardiovasc Res 92(3):375-84 |
| abstractText | AIMS: Mutations in the ALK1 gene, coding for an endothelial-specific receptor of the transforming growth factor-beta 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. METHODS AND 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. CONCLUSION: 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. |
