| First Author | Levi M | Year | 2001 |
| Journal | Circulation | Volume | 103 |
| Issue | 15 | Pages | 2014-20 |
| PubMed ID | 11306532 | Mgi Jnum | J:135010 |
| Mgi Id | MGI:3790251 | Doi | 10.1161/01.cir.103.15.2014 |
| Citation | Levi M, et al. (2001) Deficiency of urokinase-type plasminogen activator-mediated plasmin generation impairs vascular remodeling during hypoxia-induced pulmonary hypertension in mice. Circulation 103(15):2014-20 |
| abstractText | BACKGROUND: Chronic hypoxia results in the development of pulmonary hypertension and subsequent right heart failure. A role of the plasminogen system in the pathogenesis of pulmonary hypertension and pulmonary vascular remodeling has been suggested. METHODS AND RESULTS: Mice with targeted deficiency of the gene encoding tissue-type plasminogen activator (t-PA(-/-)), urokinase-type plasminogen activator (u-PA(-/-)), u-PA receptor (u-PAR(-/-)), or plasminogen (plg(-/-)) were subjected to hypoxic conditions. Hypoxia caused a significant 2.5-fold rise in right ventricular pressure in wild-type mice. Deficiency of u-PA or plasminogen prevented this increase in right ventricular pressure, t-PA(-/-) mice showed changes that were fully comparable with wild-type mice, and u-PAR(-/-) mice showed a partial response. Hypoxia induced an increase in smooth muscle cells within pulmonary arterial walls and a vascular rarefaction in the lungs of wild-type but not of u-PA(-/-) or plg(-/-) mice. Elastic lamina fragmentation, observed in hypoxic wild-type but not in u-PA or plasminogen-deficient mice, suggested that proliferation of vascular smooth muscle cells was dependent on u-PA-mediated elastic membrane degradation. Hypoxia-induced right ventricular remodeling in wild-type mice, characterized by cardiomyocyte hypertrophy and increased collagen contents, was not seen in u-PA(-/-) and plg(-/-) mice. CONCLUSIONS: Loss of the u-PA or plasminogen gene protects against the development of hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. These observations point to an essential role of u-PA-mediated plasmin generation in the adaptive response to chronic hypoxia and the occurrence of hypoxic pulmonary vascular disease. |
