Deficiency of Urokinase-Type Plasminogen Activator–Mediated Plasmin Generation Impairs Vascular Remodeling During Hypoxia-Induced Pulmonary Hypertension in Mice

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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 hypo...