title: Deficiency of urokinase-type plasminogen activator-mediated plasmin generation impairs vascular remodeling during hypoxia-induced pulmonary hypertension in mice.
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.
  
  
  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.
authors: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Belgium.
authors: M
authors: M
authors: Levi
authors: L
authors: L
authors: Moons
authors: A
authors: A
authors: Bouché
authors: S D
authors: SD
authors: Shapiro
authors: D
authors: D
authors: Collen
authors: P
authors: P
authors: Carmeliet
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D001835:Body Weight; D006439:Hemodynamics / Q000235:genetics; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D010958:Plasminogen / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D011652:Pulmonary Circulation / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9