A Review of Transcriptome Analysis in Pulmonary Vascular Diseases

  • Dustin R. Fraidenburg
  • Roberto F. Machado
Part of the Methods in Molecular Biology book series (MIMB, volume 1783)


Transcriptome analysis is a powerful tool in the study of pulmonary vascular disease and pulmonary hypertension. Pulmonary hypertension is a disease process that consists of several unique pathologies sharing a common clinical definition, that of elevated pressure within the pulmonary circulation. As such, it has become increasingly important to identify both similarities and differences among the different classes of pulmonary hypertension. Transcriptome analysis has been an invaluable tool both in the basic science research on animal models as well as clinical research among the various different groups of pulmonary hypertension. This work has identified new potential candidate genes, implicated numerous biochemical and molecular pathways in diseased onset and progression, developed gene signatures to appropriately classify types of pulmonary hypertension and severity of illness, and identified novel gene mutations leading to hereditary forms of the disease.

Key words

Pulmonary hypertension Pulmonary vascular disease Animal models BMPR2 Hereditary pulmonary arterial hypertension Lung disease 


  1. 1.
    Deng Z, Morse JH, Slager SL et al (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737–744CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    International PPHC, Lane KB, Machado RD et al (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81–84CrossRefGoogle Scholar
  3. 3.
    Taichman DB, Mandel J, Smith KA et al (2015) Pulmonary arterial hypertension. In: Grippi MA, Elias JA, Fishman JA et al (eds) Fishman’s pulmonary diseases and disorders. McGraw-Hill Education, New York, NY, p 5eGoogle Scholar
  4. 4.
    Stenmark KR, Durmowicz AG, Dempsey EC (1995) Modulation of vascular wall cell phyenotype in pulmonary hypertension. In: Bishop JE, Reeves JJ, Laurent GJ (eds) Pulmonary vascular remodeling. Portland Press, LondonGoogle Scholar
  5. 5.
    Hishikawa K, Nakaki T, Marumo T et al (1994) Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells. J Clin Invest 93:1975–1980CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Heath D, Smith P, Gosney J et al (1987) The pathology of the early and late stages of primary pulmonary hypertension. Br Heart J 58:204–213CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mandegar M, Fung YC, Huang W et al (2004) Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc Res 68:75–103CrossRefPubMedGoogle Scholar
  8. 8.
    Pietra GG (1997) The pathology of primary pulmonary hypertension. In: Rubin LJ, Rich S (eds) Primary pulmonary hypertension. Marcel Dekker, Inc, New York, NY, pp 19–61Google Scholar
  9. 9.
    Olschewski H, Rose F, Schermuly R et al (2004) Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther 102:139–153CrossRefPubMedGoogle Scholar
  10. 10.
    Levin ER (1995) Endothelins. N Engl J Med 333:356–363CrossRefPubMedGoogle Scholar
  11. 11.
    Yanagisawa M, Kurihara H, Kimura S et al (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415CrossRefPubMedGoogle Scholar
  12. 12.
    Giaid A, Yanagisawa M, Langleben D et al (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732–1739CrossRefPubMedGoogle Scholar
  13. 13.
    Kuhr FK, Smith KA, Song MY et al (2012) New mechanisms of pulmonary arterial hypertension: role of Ca2+ signaling. Am J Physiol Heart Circ Physiol 302:H1546–H1562CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Morrell NW, Adnot S, Archer SL et al (2009) Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 54:S20–S31CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bohuslavova R, Kolar F, Kuthanova L et al (2010) Gene expression profiling of sex differences in HIF1-dependent adaptive cardiac responses to chronic hypoxia. J Appl Physiol (1985) 109:1195–1202CrossRefGoogle Scholar
  16. 16.
    Veith C, Schermuly RT, Brandes RP et al (2016) Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension. J Physiol 594:1167–1177CrossRefPubMedGoogle Scholar
  17. 17.
    Buermans HP, Redout EM, Schiel AE et al (2005) Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics 21:314–323CrossRefPubMedGoogle Scholar
  18. 18.
    Kreymborg K, Uchida S, Gellert P et al (2010) Identification of right heart-enriched genes in a murine model of chronic outflow tract obstruction. J Mol Cell Cardiol 49:598–605CrossRefPubMedGoogle Scholar
  19. 19.
    Drake JI, Bogaard HJ, Mizuno S et al (2011) Molecular signature of a right heart failure program in chronic severe pulmonary hypertension. Am J Respir Cell Mol Biol 45:1239–1247CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kelly NJ, Radder JE, Baust JJ et al (2017) Mouse Genome-Wide Association study of preclinical group II pulmonary hypertension identifies epidermal growth factor receptor. Am J Respir Cell Mol Biol 56:488–496CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Vaszar LT, Nishimura T, Storey JD et al (2004) Longitudinal transcriptional analysis of developing neointimal vascular occlusion and pulmonary hypertension in rats. Physiol Genomics 17:150–156CrossRefPubMedGoogle Scholar
  22. 22.
    van Albada ME, Bartelds B, Wijnberg H et al (2010) Gene expression profile in flow-associated pulmonary arterial hypertension with neointimal lesions. Am J Physiol Lung Cell Mol Physiol 298:L483–L491CrossRefPubMedGoogle Scholar
  23. 23.
    Greco S, Gorospe M, Martelli F (2015) Noncoding RNA in age-related cardiovascular diseases. J Mol Cell Cardiol 83:142–155CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Vencken SF, Greene CM, McKiernan PJ (2015) Non-coding RNA as lung disease biomarkers. Thorax 70:501–503CrossRefPubMedGoogle Scholar
  25. 25.
    Wang X, Yan C, Xu X et al (2016) Long noncoding RNA expression profiles of hypoxic pulmonary hypertension rat model. Gene 579:23–28CrossRefPubMedGoogle Scholar
  26. 26.
    Caruso P, MacLean MR, Khanin R et al (2010) Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol 30:716–723CrossRefPubMedGoogle Scholar
  27. 27.
    Xiao T, Xie L, Huang M et al (2017) Differential expression of microRNA in the lungs of rats with pulmonary arterial hypertension. Mol Med Rep 15:591–596CrossRefPubMedGoogle Scholar
  28. 28.
    Schlosser K, White RJ, Stewart DJ (2013) miR-26a linked to pulmonary hypertension by global assessment of circulating extracellular microRNAs. Am J Respir Crit Care Med 188:1472–1475CrossRefPubMedGoogle Scholar
  29. 29.
    Xu YP, He Q, Shen Z et al (2017) MiR-126a-5p is involved in the hypoxia-induced endothelial-to-mesenchymal transition of neonatal pulmonary hypertension. Hypertens Res 40:552CrossRefPubMedGoogle Scholar
  30. 30.
    Schlosser K, Taha M, Deng Y et al (2015) Discordant regulation of microRNA between multiple experimental models and human pulmonary hypertension. Chest 148:481–490CrossRefPubMedGoogle Scholar
  31. 31.
    Gubrij IB, Pangle AK, Pang L et al (2016) Reversal of microRNA dysregulation in an animal model of pulmonary hypertension. PLoS One 11:e0147827CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Reddy S, Zhao M, Hu DQ et al (2012) Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure. Physiol Genomics 44:562–575CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Paulin R, Sutendra G, Gurtu V et al (2015) A miR-208-Mef2 axis drives the decompensation of right ventricular function in pulmonary hypertension. Circ Res 116:56–69CrossRefPubMedGoogle Scholar
  34. 34.
    Weir EK, Tucker A, Reeves JT et al (1974) The genetic factor influencing pulmonary hypertension in cattle at high altitude. Cardiovasc Res 8:745–749CrossRefPubMedGoogle Scholar
  35. 35.
    Will DH, Hicks JL, Card CS et al (1975) Inherited susceptibility of cattle to high-altitude pulmonary hypertension. J Appl Physiol 38:491–494CrossRefPubMedGoogle Scholar
  36. 36.
    Newman JH, Holt TN, Cogan JD et al (2015) Increased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension. Nat Commun 6:6863CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Newman JH, Holt TN, Hedges LK et al (2011) High-altitude pulmonary hypertension in cattle (brisket disease): candidate genes and gene expression profiling of peripheral blood mononuclear cells. Pulm Circ 1:462–469CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Heaton MP, Smith TP, Carnahan JK et al (2016) Using diverse U.S. beef cattle genomes to identify missense mutations in EPAS1, a gene associated with pulmonary hypertension. F1000Res 5:2003PubMedPubMedCentralGoogle Scholar
  39. 39.
    Gale DP, Harten SK, Reid CD et al (2008) Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation. Blood 112:919–921CrossRefPubMedGoogle Scholar
  40. 40.
    Hickey MM, Richardson T, Wang T et al (2010) The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J Clin Invest 120:827–839CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Pavlidis HO, Balog JM, Stamps LK et al (2007) Divergent selection for ascites incidence in chickens. Poult Sci 86:2517–2529CrossRefPubMedGoogle Scholar
  42. 42.
    Muir WM, Wong GK, Zhang Y et al (2008) Genome-wide assessment of worldwide chicken SNP genetic diversity indicates significant absence of rare alleles in commercial breeds. Proc Natl Acad Sci U S A 105:17312–17317CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Liu P, Yang F, Zhuang Y et al (2017) Dysregulated expression of microRNAs and mRNAs in pulmonary artery remodeling in ascites syndrome in broiler chickens. Oncotarget 8:1993–2007PubMedGoogle Scholar
  44. 44.
    Newman JH, Wheeler L, Lane KB et al (2001) Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 345:319–324CrossRefPubMedGoogle Scholar
  45. 45.
    Thomson JR, Machado RD, Pauciulo MW et al (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 37:741–745CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cogan JD, Pauciulo MW, Batchman AP et al (2006) High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 174:590–598CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Machado RD, Aldred MA, James V et al (2006) Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27:121–132CrossRefPubMedGoogle Scholar
  48. 48.
    Newman JH, Trembath RC, Morse JA et al (2004) Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol 43:33S–39SCrossRefPubMedGoogle Scholar
  49. 49.
    Shintani M, Yagi H, Nakayama T et al (2009) A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet 46:331–337CrossRefPubMedGoogle Scholar
  50. 50.
    Austin ED, Loyd JE (2014) The genetics of pulmonary arterial hypertension. Circ Res 115:189–202CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Chaouat A, Coulet F, Favre C et al (2004) Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 59:446–448CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Trembath RC, Thomson JR, Machado RD et al (2001) Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345:325–334CrossRefPubMedGoogle Scholar
  53. 53.
    Austin ED, Ma L, LeDuc C et al (2012) Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 5:336–343CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ma L, Roman-Campos D, Austin ED et al (2013) A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 369:351–361CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Maloney JP, Stearman RS, Bull TM et al (2012) Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 302:L541–L554CrossRefPubMedGoogle Scholar
  56. 56.
    Bull TM, Coldren CD, Moore M et al (2004) Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. Am J Respir Crit Care Med 170:911–919CrossRefPubMedGoogle Scholar
  57. 57.
    Risbano MG, Meadows CA, Coldren CD et al (2010) Altered immune phenotype in peripheral blood cells of patients with scleroderma-associated pulmonary hypertension. Clin Transl Sci 3:210–218CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Grigoryev DN, Mathai SC, Fisher MR et al (2008) Identification of candidate genes in scleroderma-related pulmonary arterial hypertension. Transl Res 151:197–207CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    West JD, Austin ED, Gaskill C et al (2014) Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension. Am J Physiol Cell Physiol 307:C415–C430CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Gaskill C, Marriott S, Pratap S et al (2016) Shared gene expression patterns in mesenchymal progenitors derived from lung and epidermis in pulmonary arterial hypertension: identifying key pathways in pulmonary vascular disease. Pulm Circ 6:483–497CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Germain M, Eyries M, Montani D et al (2013) Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 45:518–521CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Hemnes AR, Zhao M, West J et al (2016) Critical genomic networks and vasoreactive variants in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 194:464–475CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Sarrion I, Milian L, Juan G et al (2015) Role of circulating miRNAs as biomarkers in idiopathic pulmonary arterial hypertension: possible relevance of miR-23a. Oxid Med Cell Longev 2015:792846CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Courboulin A, Paulin R, Giguere NJ et al (2011) Role for miR-204 in human pulmonary arterial hypertension. J Exp Med 208:535–548CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Parikh VN, Jin RC, Rabello S et al (2012) MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation 125:1520–1532CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Casali L, Carratu P, Sofia M (2013) Clinical variability of respiratory pulmonary hypertension: implications for diagnosis and management. Multidiscip Respir Med 8:72CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Chaouat A, Bugnet AS, Kadaoui N et al (2005) Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 172:189–194CrossRefPubMedGoogle Scholar
  68. 68.
    Barbera JA, Peinado VI, Santos S (2003) Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J 21:892–905CrossRefPubMedGoogle Scholar
  69. 69.
    Garcia-Lucio J, Argemi G, Tura-Ceide O et al (2016) Gene expression profile of angiogenic factors in pulmonary arteries in COPD: relationship with vascular remodeling. Am J Physiol Lung Cell Mol Physiol 310:L583–L592CrossRefPubMedGoogle Scholar
  70. 70.
    Patel NM, Kawut SM, Jelic S et al (2013) Pulmonary arteriole gene expression signature in idiopathic pulmonary fibrosis. Eur Respir J 41:1324–1330CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Hoffmann J, Wilhelm J, Marsh LM et al (2014) Distinct differences in gene expression patterns in pulmonary arteries of patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis with pulmonary hypertension. Am J Respir Crit Care Med 190:98–111CrossRefPubMedGoogle Scholar
  72. 72.
    Pengo V, Lensing AW, Prins MH et al (2004) Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 350:2257–2264CrossRefPubMedGoogle Scholar
  73. 73.
    Gu S, Su P, Yan J et al (2014) Comparison of gene expression profiles and related pathways in chronic thromboembolic pulmonary hypertension. Int J Mol Med 33:277–300CrossRefPubMedGoogle Scholar
  74. 74.
    Lindner J, Maruna P, Kunstyr J et al (2009) Hemodynamic instability after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension correlates with cytokine network hyperstimulation. Eur Surg Res 43:39–46CrossRefPubMedGoogle Scholar
  75. 75.
    Wynants M, Quarck R, Ronisz A et al (2012) Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension. Eur Respir J 40:886–894CrossRefPubMedGoogle Scholar
  76. 76.
    Wang L, Guo LJ, Liu J et al (2013) MicroRNA expression profile of pulmonary artery smooth muscle cells and the effect of let-7d in chronic thromboembolic pulmonary hypertension. Pulm Circ 3:654–664CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Parent F, Bachir D, Inamo J et al (2011) A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med 365:44–53CrossRefPubMedGoogle Scholar
  78. 78.
    Desai AA, Zhou T, Ahmad H et al (2012) A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease. Am J Respir Crit Care Med 186:359–368CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Singla S, Zhou T, Javaid K et al (2016) Expression profiling elucidates a molecular gene signature for pulmonary hypertension in sarcoidosis. Pulm Circ 6:465–471CrossRefPubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Division of Pulmonary, Critical Care, Sleep and Allergy, Department of MedicineUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Department of MedicineIndiana University School of MedicineIndianapolisUSA

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