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Pulmonary Hypertension and the Extracellular Matrix

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Textbook of Pulmonary Vascular Disease

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Abstract

The extracellular matrix (ECM) plays a pivotal role in regulating cell shape and cell signaling, in maintaining cell–cell communication, and in controlling cell differentiation and dedifferentiation. The stiffness of a vessel is directly related to the proportion of the various ECM components. It is not surprising then that even haploinsufficiency of a single component of the ECM such as elastin or fibrillin can lead to profound developmental abnormalities and propensity to diseases of blood vessels. For example, haploinsufficiency of elastin (Williams syndrome) is associated with pulmonary and systemic stenoses and haploinsufficiency of fibrillin (Marfan syndrome) leads to aneurismal dilatation of the aorta. A variety of growth factors and cytokines regulate the production of the various components of the ECM and are in fact bound by different components of the ECM. Turnover of the ECM and release of growth factors is controlled by the balance between proteolytic enzymes such as serine elastases and matrix metalloproteinases (MMPs) and their endogenous inhibitors. So it is not surprising that abnormalities in the regulation of the ECM would contribute in a fundamental way to the pathobiology of pulmonary vascular disease leading to pulmonary arterial hypertension (PAH).

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References

  1. Rabinovitch M, Bothwell T, Hayakawa BN et al (1986) Pulmonary artery endothelial abnormalities in patients with congenital heart defects and pulmonary hypertension: a correlation of light with scanning electron microscopy and transmission electron microscopy. Lab Invest 55:632–653

    PubMed  CAS  Google Scholar 

  2. Aiello VD, Gutierrez PS, Chaves MJ, Lopes AA, Higuchi ML, Ramires JA (2003) Morphology of the internal elastic lamina in arteries from pulmonary hypertensive patients: a confocal laser microscopy study. Mod Pathol 16:411–416

    Article  PubMed  Google Scholar 

  3. Rosenberg HC, Rabinovitch M (1988) Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension. Am J Physiol 255:H1484–H1491

    PubMed  CAS  Google Scholar 

  4. Todorovich-Hunter L, Dodo H, Ye C, McCready L, Keeley FW, Rabinovitch M (1992) Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am Rev Respir Dis 146:213–223

    PubMed  CAS  Google Scholar 

  5. Ye C, Rabinovitch M (1991) Inhibition of elastolysis by SC-37698 reduces development and progression of monocrotaline pulmonary hypertension. Am J Physiol 261:H1255–H1267

    PubMed  CAS  Google Scholar 

  6. Spiekerkoetter E, Alvira CM, Kim YM et al (2008) Reactivation of γHV68 induces neointimal lesions in pulmonary arteries of S100A4/Mts1 over-expressing mice in association with degradation of elastin. Am J Physiol Lung Cell Mol Physiol 294:L276–L289

    Article  PubMed  CAS  Google Scholar 

  7. Thompson K, Kobayashi J, Childs T, Wigle D, Rabinovitch M (1998) Endothelial and serum factors which include apolipoprotein A1 tether elastin to smooth muscle cells inducing serine elastase activity via tyrosine kinase-mediated transcription and translation. J Cell Physiol 174:78–89

    Article  PubMed  CAS  Google Scholar 

  8. Mitani Y, Zaidi SHE, Dufourcq P, Thompson K, Rabinovitch M (2000) Nitric oxide reduces vascular smooth muscle cell elastase activity through cGMPmediated suppression of ERK phosphorylation and AML1B nuclear partitioning. FASEB J 14:805–814

    PubMed  CAS  Google Scholar 

  9. Thompson K, Rabinovitch M (1996) Exogenous leukocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular-matrix bound basic fibroblast growth factor. J Cell Physiol 166:495–505

    Article  PubMed  CAS  Google Scholar 

  10. Hinek A, Molossi S, Rabinovitch M (1996) Exploration of the molecular mechanisms leading to upregulation of fibronectin production by the arterial smooth muscle cells. Exp Cell Res 225:111–120

    Article  Google Scholar 

  11. Rabinovitch M (2007) Pathobiology of pulmonary hypertension. Annu Rev Pathol 2:369–399

    Article  PubMed  CAS  Google Scholar 

  12. Houghton AM, Quintero PA, Perkins DL et al (2006) Elastin fragments drive disease progression in a murine model of emphysema. J Clin Invest 116:753–759

    Article  PubMed  CAS  Google Scholar 

  13. Hinek A, Rabinovitch M (1993) The ductus arteriosus migratory smooth muscle cell phenotype processes tropoelastin to a 52-kDa product associated with impaired assembly of elastic laminae. J Biol Chem 268:1405–1413

    PubMed  CAS  Google Scholar 

  14. Karnik SK, Brooke BS, Bayes-Genis A et al (2003) A critical role for elastin signaling in vascular morphogenesis and disease. Development 130:411–423

    Article  PubMed  CAS  Google Scholar 

  15. Nagase H, Enghild J, Suzuki K, Salvesen G (1990) Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4-aminophenyl) mercuric acetate. Biochemistry 29:5783–5789

    Article  PubMed  CAS  Google Scholar 

  16. Jones P, Crack J, Rabinovitch M (1997) Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the αvβ3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J Cell Biol 139:279–293

    Article  PubMed  CAS  Google Scholar 

  17. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M (2000) Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 6:698–702

    Article  PubMed  CAS  Google Scholar 

  18. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M (2005) Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112:423–431

    Article  PubMed  CAS  Google Scholar 

  19. Vieillard-Baron A, Frisdal E, Eddahibi S et al (2000) Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats. Circ Res 87:418–425

    PubMed  CAS  Google Scholar 

  20. El-Bizri N, Guignabert C, Wang L et al (2008) SM22α-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis. Development 135:2981–2991

    Article  PubMed  CAS  Google Scholar 

  21. El-Bizri N, Wang L, Merklinger SL et al (2008) Smooth muscle protein 22α-mediated patchy deletion of Bmpr1a impairs cardiac contractility but protects against pulmonary vascular remodeling. Circ Res 102:380–388

    Article  PubMed  CAS  Google Scholar 

  22. Tozzi C, Thakker-Varia S, Yu S et al (1998) Mast cell collagenase correlates with regression of pulmonary vascular remodeling in the rat. Am J Respir Cell Mol Biol 18:497–510

    PubMed  CAS  Google Scholar 

  23. Zaidi SHE, Hui C-C, Cheah AYL, You X-M, Husain M, Rabinovitch M (1999) Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis. J Clin Invest 103:1211–1219

    Article  PubMed  CAS  Google Scholar 

  24. Sallenave J-M, Ryle AP (1991) Purification and characterization of elastase-specific inhibitor: Sequence homology with mucous proteinase inhibitor. Biol Chem Hoppe Seyler 372:13–21

    Article  PubMed  CAS  Google Scholar 

  25. Wiedow O, Luademann J, Utecht B (1991) Elafin is a potent inhibitor of proteinase 3. Biochem Biophys Res Commun 174:6–10

    Article  PubMed  CAS  Google Scholar 

  26. Moreau T, Baranger K, Dade S, Dallet-Choisy S, Guyot N, Zani ML (2008) Multifaceted roles of human elafin and secretory leukocyte proteinase inhibitor (SLPI), two serine protease inhibitors of the chelonianin family. Biochimie 90:284–295

    Article  PubMed  CAS  Google Scholar 

  27. Zaidi SHE, You X-M, Ciura S, Husain M, Rabinovitch M (2002) Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 105:516–521

    Article  PubMed  CAS  Google Scholar 

  28. Ohta K, Nakajima T, Cheah AY et al (2004) Elafin-overexpressing mice have improved cardiac function after myocardial infarction. Am J Physiol Heart Circ Physiol 287:H286–H292

    Article  PubMed  CAS  Google Scholar 

  29. Zaidi SH, You XM, Ciura S, O’Blenes S, Husain M, Rabinovitch M (2000) Suppressed smooth muscle proliferation and inflammatory cell invasion after arterial injury in elafin-overexpressing mice. J Clin Invest 105:1687–1695

    Article  PubMed  CAS  Google Scholar 

  30. O’Blenes SB, Zaidi SHE, Cheah AYL, McIntyre B, Kaneda Y, Rabinovitch M (2000) Gene transfer of the serine elastase inhibitor elafin protects against vein graft degeneration. Circulation 102:III289–III295

    PubMed  Google Scholar 

  31. Cowan B, Baron O, Crack J, Coulber C, Wilson GJ, Rabinovitch M (1996) Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits after heterotopic cardiac transplantation. J Clin Invest 97:2452–2468

    Article  PubMed  CAS  Google Scholar 

  32. Hirano E, Knutsen RH, Sugitani H, Ciliberto CH, Mecham RP (2007) Functional rescue of elastin insufficiency in mice by the human elastin gene: implications for mouse models of human disease. Circ Res 101:523–531

    Article  PubMed  CAS  Google Scholar 

  33. Shifren A, Durmowicz AG, Knutsen RH, Faury G, Mecham RP (2008) Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure. J Appl Physiol 105:1610–1619

    Article  PubMed  Google Scholar 

  34. Prosser IW, Stenmark KR, Suthar M, Crouch EC, Mecham RP, Parks WC (1989) Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridization. Am J Pathol 135:1073–1088

    PubMed  CAS  Google Scholar 

  35. Todorovich-Hunter L, Ranger P, Johnson D, Keeley F, Rabinovitch M (1988) Altered elastin and collagen synthesis associated with progressive pulmonary hypertensin induced by monocrotaline. A biochemical and ultrastructural study. Lab Invest 58:184–195

    PubMed  CAS  Google Scholar 

  36. Yanagisawa H, Davis EC, Starcher BC et al (2002) Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415:168–171

    Article  PubMed  Google Scholar 

  37. Merklinger SL, Wagner RA, Spiekerkoetter E et al (2005) Increased fibulin-5 and elastin in S100A4/Mts1 mice with pulmonary hypertension. Circ Res 97:596–604

    Article  PubMed  CAS  Google Scholar 

  38. Greenway S, van Suylen RJ (2004) Du Marchie Sarvaas G, et al. S100A4/Mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol 164:253–262

    Article  PubMed  CAS  Google Scholar 

  39. Morse JH, Antohi S, Kasturi K et al (2000) Fine specificity of anti-fibrillin-1 autoantibodies in primary pulmonary hypertension syndrome. Scand J Immunol 51:607–611

    Article  PubMed  CAS  Google Scholar 

  40. Ihida-Stansbury K, McKean DM, Lane KB et al (2006) Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 291:L694–L702

    Article  PubMed  CAS  Google Scholar 

  41. McKean DM, Sisbarro L, Ilic D et al (2003) FAK induces expression of Prx1 to promote tenascin-C-dependent fibroblast migration. J Cell Biol 161:393–402

    Article  PubMed  CAS  Google Scholar 

  42. Jones FS, Meech R, Edelman DB, Oakey RJ, Jones PL (2001) Prx1 controls vascular smooth muscle cell proliferation and tenascin-C expression and is upregulated with Prx2 in pulmonary vascular disease. Circ Res 89:131–138

    Article  PubMed  CAS  Google Scholar 

  43. Jones PL, Cowan KN, Rabinovitch M (1997) Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol 150:1349–1360

    PubMed  CAS  Google Scholar 

  44. Cowan KN, Jones PL, Rabinovitch M (2000) Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression of vascular disease. J Clin Invest 105:21–34

    Article  PubMed  CAS  Google Scholar 

  45. Boudreau N, Turley E, Rabinovitch M (1991) Fibronectin, hyaluronan, and a hyaluronan binding protein contribute to increased ductus arteriosus smooth muscle cell migration. Dev Biol 143:235–247

    Article  PubMed  CAS  Google Scholar 

  46. Pozzetto U, Aguzzi MS, Maggiano N et al (2005) RGDS peptide inhibits activation of lymphocytes and adhesion of activated lymphocytes to human umbilical vein endothelial cells in vitro. Immunol Cell Biol 83:25–32

    Article  PubMed  CAS  Google Scholar 

  47. Botney MD, Liptay MJ, Kaiser LR, Cooper JD, Parks WC, Mecham RP (1993) Active collagen synthesis by pulmonary arteries in human primary pulmonary hypertension. Am J Pathol 143:121–129

    PubMed  CAS  Google Scholar 

  48. Frid MG, Brunetti JA, Burke DL et al (2006) Hypoxia-induced ­pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 168:659–669

    Article  PubMed  CAS  Google Scholar 

  49. Hwang JY, Johnson PY, Braun KR et al (2008) Retrovirally mediated overexpression of glycosaminoglycan-deficient biglycan in arterial smooth muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointimae after vascular injury. Am J Pathol 173:1919–1928

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pediatrics, Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, CCSR-Room 2245B, 269 Campus Drive, Stanford, CA, 94305-5162, USA

    Marlene Rabinovitch

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  1. Marlene Rabinovitch
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Correspondence to Marlene Rabinovitch .

Editor information

Editors and Affiliations

  1. Departments of Medicine, COMRB Rm. 3131 (MC 719), University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, 60612, Illinois, USA

    Jason X. -J. Yuan

  2. 310 Admin.Office Building (MC 672), University of Illinois at Chicago, 1737 W. Polk Street, Suite 310, Chicago, 60612, Illinois, USA

    Joe G.N. Garcia

  3. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0623, California, USA

    John B. West

  4. Dept. Pulmonary & Critical Care Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Charles A. Hales

  5. Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Stuart Rich

  6. Department of Medicine, University of Chicago School of Medicine, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Stephen L. Archer

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Rabinovitch, M. (2011). Pulmonary Hypertension and the Extracellular Matrix. In: Yuan, JJ., Garcia, J., West, J., Hales, C., Rich, S., Archer, S. (eds) Textbook of Pulmonary Vascular Disease. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-87429-6_55

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  • DOI: https://doi.org/10.1007/978-0-387-87429-6_55

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  • Publisher Name: Springer, Boston, MA

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  • Online ISBN: 978-0-387-87429-6

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