This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Levi, M. Articles by Carmeliet, P. Search for Related Content PubMed PubMed Citation Articles by Levi, M. Articles by Carmeliet, P. Related Collections Remodeling Hypertrophy Pulmonary circulation and disease

(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

Marcel Levi, MD, PhD; Lieve Moons, PhD; Ann Bouché; Steve D. Shapiro, MD; Desiré Collen, MD, PhD; Peter Carmeliet, MD, PhD

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

This article has been cited by other articles:

				R. Krishnan, M. Kremen, J. H. Hu, I. Emery, S. D. Farris, K. I. Slezicki, T. Chu, L. Du, H. L. Dichek, and D. A. Dichek Level of Macrophage uPA Expression Is an Important Determinant of Atherosclerotic Lesion Growth in Apoe-/- Mice Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1737 - 1744. [Abstract] [Full Text] [PDF]

				K.-O. Larsen, B. Lygren, I. Sjaastad, K. A. Krobert, K. Arnkvaern, G. Florholmen, A.-K. R. Larsen, F. O. Levy, K. Tasken, O. H. Skjonsberg, et al. Diastolic dysfunction in alveolar hypoxia: a role for interleukin-18-mediated increase in protein phosphatase 2A Cardiovasc Res, October 1, 2008; 80(1): 47 - 54. [Abstract] [Full Text] [PDF]

				L. De Franceschi, O. S. Platt, G. Malpeli, A. Janin, A. Scarpa, C. Leboeuf, Y. Beuzard, E. Payen, and C. Brugnara Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice FASEB J, June 1, 2008; 22(6): 1849 - 1860. [Abstract] [Full Text] [PDF]

				P. McLoughlin and I. McMurtry Counterpoint: Chronic Hypoxia-induced Pulmonary Hypertension does not Lead to Loss of Pulmonary Vasculature J Appl Physiol, October 1, 2007; 103(4): 1451 - 1453. [Full Text] [PDF]

				M. Rabinovitch, N. Chesler, and R. C. Molthen Point:Counterpoint: Chronic hypoxia-induced pulmonary hypertension does/does not lead to loss of pulmonary vasculature J Appl Physiol, October 1, 2007; 103(4): 1449 - 1451. [Full Text] [PDF]

				Y. Hou, C. Okamoto, K. Okada, N. Kawao, S. Kawata, S. Ueshima, and O. Matsuo c-Myc is essential for urokinase plasminogen activator expression on hypoxia-induced vascular smooth muscle cells Cardiovasc Res, July 1, 2007; 75(1): 186 - 194. [Abstract] [Full Text] [PDF]

				K.-O. Larsen, I. Sjaastad, A. Svindland, K. A. Krobert, O. H. Skjonsberg, and G. Christensen Alveolar hypoxia induces left ventricular diastolic dysfunction and reduces phosphorylation of phospholamban in mice Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H507 - H516. [Abstract] [Full Text] [PDF]

				S. L. Merklinger, R. A. Wagner, E. Spiekerkoetter, A. Hinek, R. H. Knutsen, M. G. Kabir, K. Desai, S. Hacker, L. Wang, G. M. Cann, et al. Increased Fibulin-5 and Elastin in S100A4/Mts1 Mice With Pulmonary Hypertension Circ. Res., September 16, 2005; 97(6): 596 - 604. [Abstract] [Full Text] [PDF]

				C. Otto, L. Hein, M. Brede, R. Jahns, S. Engelhardt, H.-J. Grone, and G. Schutz Pulmonary Hypertension and Right Heart Failure in Pituitary Adenylate Cyclase-Activating Polypeptide Type I Receptor-Deficient Mice Circulation, November 16, 2004; 110(20): 3245 - 3251. [Abstract] [Full Text] [PDF]

				T. Nishiuma, T. H. Sisson, N. Subbotina, and R. H. Simon Localization of Plasminogen Activator Activity within Normal and Injured Lungs by In Situ Zymography Am. J. Respir. Cell Mol. Biol., November 1, 2004; 31(5): 552 - 558. [Abstract] [Full Text] [PDF]

				T. M. Razzaq, R. Bass, D. J. Vines, F. Werner, S. A. Whawell, and V. Ellis Functional Regulation of Tissue Plasminogen Activator on the Surface of Vascular Smooth Muscle Cells by the Type-II Transmembrane Protein p63 (CKAP4) J. Biol. Chem., October 24, 2003; 278(43): 42679 - 42685. [Abstract] [Full Text] [PDF]

				T. M. Hale, M. J. Shoichet, T. L. Bushfield, and M. A. Adams Time Course of Vascular Structural Changes During and After Short-Term Antihypertensive Treatment Hypertension, August 1, 2003; 42(2): 171 - 176. [Abstract] [Full Text] [PDF]

				E. Dai, H. Guan, L. Liu, S. Little, G. McFadden, S. Vaziri, H. Cao, I. A. Ivanova, L. Bocksch, and A. Lucas Serp-1, a Viral Anti-inflammatory Serpin, Regulates Cellular Serine Proteinase and Serpin Responses to Vascular Injury J. Biol. Chem., May 9, 2003; 278(20): 18563 - 18572. [Abstract] [Full Text] [PDF]

				S. Eddahibi, N. Morrell, M-P. d'Ortho, R. Naeije, and S. Adnot Pathobiology of pulmonary arterial hypertension Eur. Respir. J., December 1, 2002; 20(6): 1559 - 1572. [Abstract] [Full Text] [PDF]

				T. Nassar, A. Haj-Yehia, S.'e. Akkawi, A. Kuo, K. Bdeir, A. Mazar, D. B. Cines, and A. A.-R. Higazi Binding of Urokinase to Low Density Lipoprotein-related Receptor (LRP) Regulates Vascular Smooth Muscle Cell Contraction J. Biol. Chem., October 18, 2002; 277(43): 40499 - 40504. [Abstract] [Full Text] [PDF]