(Circulation. 2001;103:2014.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Deficiency of Urokinase-Type Plasminogen Activator–Mediated Plasmin Generation Impairs Vascular Remodeling During Hypoxia-Induced Pulmonary Hypertension in Mice
From the Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Belgium (M.L., L.M., A.B., D.C., P.C.); the Department of Vascular Medicine and Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands (M.L.); and the Department of Pediatrics, Cell Biology, and Medicine, Washington University School of Medicine, St Louis Children’s Hospital, St Louis, Mo (S.D.S.).
Correspondence to Peter Carmeliet, MD, PhD, Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Campus Gasthuisberg, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail peter.carmeliet{at}med.kuleuven.ac.be
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.
Key Words: plasminogen • plasminogen activators • pulmonary heart disease • vasculature • remodeling
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