Title: Deficiency of urokinase-type plasminogen activator-mediated plasmin generation impairs vascular remodeling during hypoxia-induced pulmonary hypertension in mice
Authors: Levi, M ×
Moons, Lieve
Bouché, A
Shapiro, S D
Collen, Desire
Carmeliet, Peter #
Issue Date: Apr-2001
Publisher: American Heart Association
Series Title: Circulation vol:103 issue:15 pages:2014-20
Abstract: 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.
ISSN: 0009-7322
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
Animal Physiology and Neurobiology Section - miscellaneous
Vesalius Research Centre (-)
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)
× corresponding author
# (joint) last author

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