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Journal Article

Hypoxic pulmonary hypertension in mice with constitutively active platelet-derived growth factor receptor-β

Bhola K. Dahal, Rainer Heuchel, Soni Savai Pullamsetti, Jochen Wilhelm, Hossein A. Ghofrani, Norbert Weissmann, Werner Seeger, Friedrich Grimminger and Ralph T. Schermuly
Pulmonary Circulation
Vol. 1, No. 2 (April 2011), pp. 259-268
DOI: 10.4103/2045-8932.83448
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Page Count: 10
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AbstractPlatelet-derived growth factor (PDGF) has been implicated in the pathobiology of vascular remodeling. The multikinase inhibitor imatinib that targets PDGF receptor (PDGFR), c-kit and Abl kinases, shows therapeutic efficacy against experimental pulmonary hypertension (PH); however, the role of PDGFR-β in experimental PH has not been examined by genetic approach. We investigated the chronic hypoxia-induced PH in mice carrying an activating point mutation of PDGFR-β (D849N) and evaluated the therapeutic efficacy of imatinib. In addition, we studied pulmonary global gene expression and confirmed the expression of identified genes by immunohistochemistry. Chronically hypoxic D849N mice developed PH and strong pulmonary vascular remodeling that was improved by imatinib (100 mg/kg/day) as evident from the significantly reduced right ventricular systolic pressure, right ventricular hypertrophy and muscularization of peripheral pulmonary arteries. Global gene expression analysis revealed that stromal cell derived factor SDF)-1αwas significantly upregulated, which was confirmed by immunohistochemistry. Moreover, an enhanced immunoreactivity for SDF-1α, PDGFR-β and CXCR4, the receptor for SDF-1α was localized to the α-smooth muscle cell (SMC) actin positive pulmonary vascular cells in hypoxic mice and patients with idiopathic pulmonary arterial hypertension (IPAH). In conclusion, our findings substantiate the major role of PDGFR activation in pulmonary vascular remodeling by a genetic approach. Immunohistochemistry findings suggest a role for SDF-1α/CXCR4 axis in pulmonary vascular remodeling and point to a potential interaction between the chemokine SDF-1 and the growth factor PDGF signaling. Future studies designed to elucidate an interaction between the chemokine SDF-1 and the PDGF system may uncover novel therapeutic targets.

Notes and References

This item contains 54 references.

  • 1.
    ['Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:13S–24.']
  • 2.
    ['Rabinovitch M. Pathobiology of pulmonary hypertension. Annu Rev Pathol 2007;2:369–99.']
  • 3.
    ['Grimminger F, Schermuly RT, Ghofrani HA. Targeting non-malignant disorders with tyrosine kinase inhibitors. Nat Rev Drug Discov 2010;9:956–70.']
  • 4.
    ['Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009;54:S10–9.']
  • 5.
    ['Graf K, Xi XP, Yang D, Fleck E, Hsueh WA, Law RE. Mitogen-activated protein kinase activation is involved in platelet-derived growth factor-directed migration by vascular smooth muscle cells. Hypertension 1997;29:334–9.']
  • 6.
    ['Heldin CH, Ostman A, Ronnstrand L. Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1998;1378:F79–113.']
  • 7.
    ['Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 1999;79:1283–316.']
  • 8.
    ['Rosenkranz S, Kazlauskas A. Evidence for distinct signaling properties and biological responses induced by the PDGF receptor alpha and beta subtypes. Growth Factors 1999;16:201–16.']
  • 9.
    ['Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev 2008;22:1276–312.']
  • 10.
    ['Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708–10.']
  • 11.
    ['Balasubramaniam V, Le Cras TD, Ivy DD, Grover TR, Kinsella JP, Abman SH. Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 2003;284:L826–33.']
  • 12.
    ['Perros F, Montani D, Dorfmuller P, Durand-Gasselin I, Tcherakian C, Le PJ, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;178:81–8.']
  • 13.
    ['Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811–21.']
  • 14.
    ['Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti JL, etal. Stromal cell-derived factor lalpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res 2003;63:1969–74.']
  • 15.
    ['Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, et al. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: A possible role for tumor progression. Clin Cancer Res 2000;6:3530–5.']
  • 16.
    ['Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S, et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res 2002;62:5930–8.']
  • 17.
    ['Porcile C, Bajetto A, Barbieri F, Barbero S, Bonavia R, Biglieri M, et al. Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation. Exp Cell Res 2005;308:241–53.']
  • 18.
    ['Hagerstrand D, Hesselager G, Achterberg S, Wickenberg BU, Kowanetz M, Kastemar M, et al. Characterization of an imatinib-sensitive subset of high-grade human glioma cultures. Oncogene 2006;25:4913–22.']
  • 19.
    ['Satoh K, Fukumoto Y, Nakano M, Sugimura K, Nawata J, Demachi J, et al. Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1. Cardiovasc Res 2009;81:226–34.']
  • 20.
    ['Schober A, Knarren S, Lietz M, Lin EA, Weber C. Crucial role of stromal cell-derived factor-1alpha in neointima formation afer vascular injury in apolipoprotein E-deficient mice. Circulation 2003;108:2491–7.']
  • 21.
    ['Shiba Y, Takahashi M, Yoshioka T, Yajima N, Morimoto H, Izawa A, etal. M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: The critical role of the SDF-1-CXCR4 system. Arterioscler Thromb Vase Biol 2007;27:283–9.']
  • 22.
    ['Zernecke A, Schober A, Bot I, von Hundelshausen P, Liehn EA, Mopps B, et al. SDF-1alpha/CXCR4 axis is instrumental in neointimal hyperplasia and recruitment of smooth muscle progenitor cells. Circ Res 2005;96:784–91.']
  • 23.
    ['Chiara F, Goumans MJ, Forsberg H, Ahgren A, Rasola A, Aspenstrom P, et al. A gain of function mutation in the activation loop of platelet-derived growth factor beta-receptor deregulates its kinase activity. J Biol Chem 2004;279:42516–27.']
  • 24.
    ['Dahal BK, Heuchel R, Pullamsetti SS, Ghofrani HA, Weissmann N, Seeger W, et al. Platelet derived growth factor receptor-β contributes to hypoxia-induced pulmonary vascular remodeling [abstract]. Am J Respir Crit Care Med 2008;177:A532.']
  • 25.
    ['Dahal BK, Cornitescu T, Tretyn A, Pullamsetti SS, Kosanovic D, Dumitrascu R, et al. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med 2010;181:158–67.']
  • 26.
    ['Schermuly RT, Pullamsetti SS, Kwapiszewska G, Dumitrascu R, Tian X, Weissmann N, et al. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: Target for reverse-remodeling therapy. Circulation 2007;115:2331–9.']
  • 27.
    ['R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available from: [Last accessed in 2007].']
  • 28.
    ['Smyth GK. Limma: Linear models for microarray data. In: Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W, editors. Bioinformatics and Computational Biology Solutions using R and Bioconductor. New York: Springer; 2005. p. 397–420.']
  • 29.
    ['Gentleman R, Carey V, Bates D, Bolstad B, Dettling M, Dudoit S, et al. Bioconductor: Open sofware development for computational biology and bioinformatics. Genome Biol 2004;5:R80.']
  • 30.
    ['Edwards D. Non-linear normalization and background correction in one-channel cDNA microarray studies. Bioinformatics 2003;19:825–33.']
  • 31.
    ['Smyth GK, Speed T. Normalization of cDNA microarray data. Methods 2003;31:265–73.']
  • 32.
    ['Smyth GK. Linear models and empirical bayes methods for assessing diferential expression in microarray experiments. Stat Appl Genet Mol Biol 2004;3:Article3.']
  • 33.
    ['Karlsson S, Kowanetz K, Sandin A, Persson C, Ostman A, Heldin CH, et al. Loss of T-cell protein tyrosine phosphatase induces recycling of the platelet-derived growth factor (PDGF) beta-receptor but not the PDGF alpha-receptor. Mol Biol Cell 2006;17:4846–55.']
  • 34.
    ['Betsholtz C. Insight into the physiological functions of PDGF through genetic studies in mice. Cytokine Growth Factor Rev 2004;15:215–28.']
  • 35.
    ['Huang M, Duhadaway JB, Prendergast GC, Laury-Kleintop LD. RhoB regulates PDGFR-β trafficking and signaling in vascular smooth muscle cells. Arterioscler Thromb Vase Biol 2007;27:2597–605.']
  • 36.
    ['Kingsley K, Huff JL, Rust WL, Carroll K, Martinez AM, Fitchmun M, et al. ERK1/2 mediates PDGF-BB stimulated vascular smooth muscle cell proliferation and migration on laminin-5. Biochem Biophys Res Commun 2002;293:1000–6.']
  • 37.
    ['Schultz K, Fanburg BL, Beasley D. Hypoxia and hypoxia-inducible factor-1alpha promote growth factor-induced proliferation of human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2006;290:H2528–34.']
  • 38.
    ['Krampert M, Heldin CH, Heuchel RL. A gain-of-function mutation in the PDGFR-β alters the kinetics of injury response in liver and skin. Lab Invest 2008;88:1204–14.']
  • 39.
    ['Suzuki S, Heldin CH, Heuchel RL. Platelet-derived growth factor receptor-beta, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma. BMC Cancer 2007;7:224.']
  • 40.
    ['Resnick N, Collins T, Atkinson W, Bonthron DT, Dewey CF Jr, Gimbron MA Jr. Platelet-derived growth factor B chain promoter contains a cis-acting fluid shear-stress-responsive element. Proc Natl Acad Sci U S A 1993;90:7908.']
  • 41.
    ['Tanabe Y, Saito M, Ueno A, Nakamura M, Takeishi K, Nakayama K. Mechanical stretch augments PDGF receptor beta expression and protein tyrosine phosphorylation in pulmonary artery tissue and smooth muscle cells. Mol Cell Biochem 2000;215:103–13.']
  • 42.
    ['Saito S, Frank GD, Mifune M, Ohba M, Utsunomiya H, Motley ED, et al. Ligand-independent trans-activation of the platelet-derived growth factor receptor by reactive oxygen species requires protein kinase C-delta and c-Src. J Biol Chem 2002;277:44695–700.']
  • 43.
    ['Gambaryan N, Perros F, Montani D, Cohen-Kaminsky S, Mazmanian GM, Humbert M. Imatinib inhibits bone marrow-derived c-kit+ cell mobilisation in hypoxic pulmonary hypertension. Eur Respir J 2010;36:1209–11.']
  • 44.
    ['Dahal BK, Kosanovic D, Kaulen C, Cornitescu T, Savai R, Hoffmann J, et al. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. Respir Res 2011;12:60.']
  • 45.
    ['Schober A, Zernecke A. Chemokines in vascular remodeling. Thromb Haemost 2007;97:730–7.']
  • 46.
    ['Teicher BA, Fricker SP CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 2010;16:2927–31.']
  • 47.
    ['Pety JM, Sueblinvong V, Lenox CC, Jones CC, Cosgrove GP, Cool CD, et al. Pulmonary stromal-derived factor-1 expression and effect on neutrophil recruitment during acute lung injury. J Immunol 2007;178:8148–57.']
  • 48.
    ['Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, et al. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004;114:438–46.']
  • 49.
    ['Walter DH, Rochwalsky U, Reinhold J, Seeger F, Aicher A, Urbich C, et al. Sphingosine-1-phosphate stimulates the functional capacity of progenitor cells by activation of the CXCR4-dependent signaling pathway via the S1P3 receptor. Arterioscler Thromb Vasc Biol 2007;27:275–82.']
  • 50.
    ['Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004;10:858–64.']
  • 51.
    ['Karshovska E, Zernecke A, Sevilmis G, Millet A, Hristov M, Cohen CD, et al. Expression of HIF-1alpha in injured arteries controls SDF-1alpha mediated neointima formation in apolipoprotein E deficient mice. Arterioscler Thromb Vase Biol 2007;27:2540–7.']
  • 52.
    ['Gambaryan N, Perros F, Montani D, Cohen-Kaminsky S, Mazmanian M, Renaud JF, et al. Targeting of c-kit+ hematopoietic progenitor cells prevents hypoxic pulmonary hypertension. Eur Respir J 2011;37:1392–9.']
  • 53.
    ['Nemenoff RA, Simpson PA, Furgeson SB, Kaplan-Albuquerque N, Crossno J, Garl PJ, et al. Targeted deletion of PTEN in smooth muscle cells results in vascular remodeling and recruitment of progenitor cells through induction of stromal cell-derived factor-1. Circ Res 2008;102:1036–45.']
  • 54.
    ['Toshner M, Voswinckel R, Southwood M, Al-Lamki R, Howard LS, Marchesan D, et al. Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir Crit Care Med 2009;180:780–7.']