Diagnosis and Pathophysiological Mechanisms of Group 3 Hypoxia-Induced Pulmonary Hypertension

  • Kel Vin Woo
  • David M. Ornitz
  • Gautam K. SinghEmail author
Pediatric and Congenital Heart Disease (G Singh, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pediatric and Congenital Heart Disease


Purpose of review

Group 3 hypoxia-induced pulmonary hypertension (PH) is an important and increasingly diagnosed condition in both the pediatric and adult population. The majority of pulmonary hypertension studies to date and all three classes of drug therapies were designed to focus on group 1 PH. There is a clear unmet medical need for understanding the molecular mechanisms of group 3 PH and a need for novel non-invasive methods of assessing PH in neonates.

Recent findings

Several growth factors are expressed in patients and in animal models of group 3 PH and are thought to contribute to the pathophysiology of this disease. Here, we review some of the findings on the roles of vascular endothelial growth factor A (VEGFA), platelet-derived growth factor B (PDGFB), transforming growth factor-beta (TGFB1), and fibroblast growth factors (FGF) in PH. Additionally, we discuss novel uses of echocardiographic parameters in assessing right ventricular form and function.


FGF2, TGFB, PDGFB, and VEGFA may serve as biomarkers in group 3 PH along with echocardiographic methods to diagnose and follow right ventricle function. FGFs and VEGFs may also function in the pathophysiology of group 3 PH.


Pulmonary hypertension Hypoxia Group 3 pulmonary hypertension Echocardiography Right ventricle Fibroblast growth factors 


Compliance with Ethical Standards

Conflict of Interest

Kel Vin Woo declares no potential conflicts of interest.

David M. Ornitz reports a grant from the NIH.

Gautam K. Singh is a section editor for Current Treatment Options in Cardiovascular Medicine.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43–54.PubMedGoogle Scholar
  2. 2.
    Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376–87.PubMedGoogle Scholar
  3. 3.
    Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126(3):443–56.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Oswald-Mammosser M, Weitzenblum E, Quoix E, Moser G, Chaouat A, Charpentier C, et al. Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest. 1995;107(5):1193–8.PubMedGoogle Scholar
  5. 5.
    Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013;158(9):641–9.PubMedGoogle Scholar
  6. 6.
    Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA, Maniscalco WM. Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1971–80.PubMedGoogle Scholar
  7. 7.
    • Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015;191(1):87–95. This is an important investigation that assessed the utility of echocardiography to identify preterm infants developing pulmonary vascular disease. Early echocardiograms may be useful in identifying patients at risk for BPD and PH.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Boucherat O, Morissette MC, Provencher S, Bonnet S, Maltais F. Bridging lung development with chronic obstructive pulmonary disease. Relevance of developmental pathways in chronic obstructive pulmonary disease pathogenesis. Am J Respir Crit Care Med. 2016;193(4):362–75.PubMedGoogle Scholar
  9. 9.
    Seeger W, Adir Y, Barberà JA, Champion H, Coghlan JG, Cottin V, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(25 Suppl):D109–16.PubMedGoogle Scholar
  10. 10.
    Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation. 2008;117(13):1717–31.PubMedGoogle Scholar
  11. 11.
    Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, et al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation. 2009;120(20):1951–60.PubMedGoogle Scholar
  12. 12.
    Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an international forum on cardiac remodeling. J Am Coll Cardiol. 2000;35(3):569–82.PubMedGoogle Scholar
  13. 13.
    Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation. 2006;114(17):1883–91.PubMedGoogle Scholar
  14. 14.
    Hopkins WE, Waggoner AD, Gussak H. Quantitative ultrasonic tissue characterization of myocardium in cyanotic adults with an unrepaired congenital heart defect. Am J Cardiol. 1994;74(9):930–4.PubMedGoogle Scholar
  15. 15.
    Pacileo G, Calabro P, Limongelli G, Verrengia M, Di Salvo G, Russo GM, et al. Feasibility and usefulness of right ventricular ultrasonic tissue characterization with integrated backscatter in patients with unsuccessfully operatively “repaired” tetralogy of Fallot. Am J Cardiol. 2002;90(6):669–71.PubMedGoogle Scholar
  16. 16.
    Pacileo G, Limongelli G, Verrengia M, Gimeno J, Di Salvo G, Calabro R. Backscatter evaluation of myocardial functional and textural findings in children with right ventricular pressure and/or volume overload. Am J Cardiol. 2004;93(5):594–7.PubMedGoogle Scholar
  17. 17.
    Pacileo G, Limongelli G, Verrengia M, Miele T, Cesare G, Calabro P, et al. Impact of pulmonary regurgitation and age at surgical repair on textural and functional right ventricular myocardial properties in patients with tetralogy of Fallot. Ital Heart J. 2005;6(9):745–50.PubMedGoogle Scholar
  18. 18.
    Waggoner AD, Perez JE, Miller JG, Sobel BE. Differentiation of normal and ischemic right ventricular myocardium with quantitative two-dimensional integrated backscatter imaging. Ultrasound Med Biol. 1992;18(3):249–53.PubMedGoogle Scholar
  19. 19.
    Yildirim N, Saricam E, Ozbakir C, Bozboga S, Ocal A. Assessment of the relationship between functional capacity and right ventricular ultrasound tissue characterization by integrated backscatter in patients with isolated mitral stenosis. Int Heart J. 2007;48(1):87–96.PubMedGoogle Scholar
  20. 20.
    Yildirim N, Tekin NS, Tekin IO, Dogan S, Aydin M, Gursurer M, et al. Myocardial functional and textural findings of the right and left ventricles and their association with cellular adhesion molecules in Behcet’s disease. Echocardiography. 2007;24(7):702–11.PubMedGoogle Scholar
  21. 21.
    Jamal F, Bergerot C, Argaud L, Loufouat J, Ovize M. Longitudinal strain quantitates regional right ventricular contractile function. Am J Physiol Heart Circ Physiol. 2003;285(6):H2842–7.PubMedGoogle Scholar
  22. 22.
    Chow PC, Liang XC, Cheung EW, Lam WW, Cheung YF. New two-dimensional global longitudinal strain and strain rate imaging for assessment of systemic right ventricular function. Heart. 2008;94(7):855–9.PubMedGoogle Scholar
  23. 23.
    Filusch A, Mereles D, Gruenig E, Buss S, Katus HA, Meyer FJ. Strain and strain rate echocardiography for evaluation of right ventricular dysfunction in patients with idiopathic pulmonary arterial hypertension. Clin Res Cardiol. 2010;99(8):491–8.PubMedGoogle Scholar
  24. 24.
    Pirat B, McCulloch ML, Zoghbi WA. Evaluation of global and regional right ventricular systolic function in patients with pulmonary hypertension using a novel speckle tracking method. Am J Cardiol. 2006;98(5):699–704.PubMedGoogle Scholar
  25. 25.
    Matias C, Isla LP, Vasconcelos M, Almeria C, Rodrigo JL, Serra V, et al. Speckle-tracking-derived strain and strain-rate analysis: a technique for the evaluation of early alterations in right ventricle systolic function in patients with systemic sclerosis and normal pulmonary artery pressure. J Cardiovasc Med (Hagerstown). 2009;10(2):129–34.Google Scholar
  26. 26.
    • Levy PT, El-Khuffash A, Patel MD, Breatnach CR, James AT, Sanchez AA, et al. Maturational patterns of systolic ventricular deformation mechanics by two-dimensional speckle-tracking echocardiography in preterm infants over the first year of age. J Am Soc Echocardiogr. 2017;30(7):685–98 e1. This investigation uses 2DSTE in a large cohort of ELGAN from birth. BPD and PH negatively impact RV strain throughout the first year of life. Deformation imaging by 2DSTE may be used early to identify impending cardiovascular compromise, and guide early intervention.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Ambalavanan N, Walsh M, Bobashev G, Das A, Levine B, Carlo WA, et al. Intercenter differences in bronchopulmonary dysplasia or death among very low birth weight infants. Pediatrics. 2011;127(1):e106–16.PubMedGoogle Scholar
  28. 28.
    Levy PT, Holland MR, Sekarski TJ, Hamvas A, Singh GK. Feasibility and reproducibility of systolic right ventricular strain measurement by speckle-tracking echocardiography in premature infants. J Am Soc Echocardiogr. 2013;26(10):1201–13.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Dunmire B, Beach KW, Labs K, Plett M, Strandness DE Jr. Cross-beam vector Doppler ultrasound for angle-independent velocity measurements. Ultrasound Med Biol. 2000;26(8):1213–35.PubMedGoogle Scholar
  30. 30.
    Kim HB, Hertzberg JR, Shandas R. Echo PIV for flow field measurements in vivo. Biomed Sci Instrum. 2004;40:357–63.PubMedGoogle Scholar
  31. 31.
    Hong GR, Pedrizzetti G, Tonti G, Li P, Wei Z, Kim JK, et al. Characterization and quantification of vortex flow in the human left ventricle by contrast echocardiography using vector particle image velocimetry. JACC Cardiovasc Imaging. 2008;1(6):705–17.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Zhang F, Lanning C, Mazzaro L, Barker AJ, Gates PE, Strain WD, et al. In vitro and preliminary in vivo validation of echo particle image velocimetry in carotid vascular imaging. Ultrasound Med Biol. 2011;37(3):450–64.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Kheradvar A, Houle H, Pedrizzetti G, Tonti G, Belcik T, Ashraf M, et al. Echocardiographic particle image velocimetry: a novel technique for quantification of left ventricular blood vorticity pattern. J Am Soc Echocardiogr. 2010;23(1):86–94.PubMedGoogle Scholar
  34. 34.
    Sengupta PP, Burke R, Khandheria BK, Belohlavek M. Following the flow in chambers. Heart Fail Clin. 2008;4(3):325–32.PubMedGoogle Scholar
  35. 35.
    Sengupta PP, Khandheria BK, Korinek J, Jahangir A, Yoshifuku S, Milosevic I, et al. Left ventricular isovolumic flow sequence during sinus and paced rhythms: new insights from use of high-resolution Doppler and ultrasonic digital particle imaging velocimetry. J Am Coll Cardiol. 2007;49(8):899–908.PubMedGoogle Scholar
  36. 36.
    Faludi R, Szulik M, D'Hooge J, Herijgers P, Rademakers F, Pedrizzetti G, et al. Left ventricular flow patterns in healthy subjects and patients with prosthetic mitral valves: an in vivo study using echocardiographic particle image velocimetry. J Thorac Cardiovasc Surg. 2010;139(6):1501–10.PubMedGoogle Scholar
  37. 37.
    Idiopathic Pulmonary Fibrosis Clinical Research N, Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363(7):620–8.Google Scholar
  38. 38.
    Jackson RM, Glassberg MK, Ramos CF, Bejarano PA, Butrous G, Gomez-Marin O. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung. 2010;188(2):115–23.PubMedGoogle Scholar
  39. 39.
    Bayer terminates phase II study with riociguat in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias [press release]. 2016.Google Scholar
  40. 40.
    Kajdaniuk D, Marek B, Borgiel-Marek H, Kos-Kudla B. Transforming growth factor beta1 (TGFbeta1) in physiology and pathology. Endokrynol Pol. 2013;64(5):384–96.PubMedGoogle Scholar
  41. 41.
    Bartram U, Speer CP. The role of transforming growth factor beta in lung development and disease. Chest. 2004;125(2):754–65.PubMedGoogle Scholar
  42. 42.
    Agrotis A, Kalinina N, Bobik A. Transforming growth factor-beta, cell signaling and cardiovascular disorders. Curr Vasc Pharmacol. 2005;3(1):55–61.PubMedGoogle Scholar
  43. 43.
    Jiang Y, Dai A, Li Q, Hu R. Hypoxia induces transforming growth factor-beta1 gene expression in the pulmonary artery of rats via hypoxia-inducible factor-1alpha. Acta Biochim Biophys Sin Shanghai. 2007;39(1):73–80.PubMedGoogle Scholar
  44. 44.
    Lu A, Zuo C, He Y, Chen G, Piao L, Zhang J, et al. EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling. J Clin Invest. 2015;125(3):1228–42.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Gilbane AJ, Derrett-Smith E, Trinder SL, Good RB, Pearce A, Denton CP, et al. Impaired bone morphogenetic protein receptor II signaling in a transforming growth factor-beta-dependent mouse model of pulmonary hypertension and in systemic sclerosis. Am J Respir Crit Care Med. 2015;191(6):665–77.PubMedGoogle Scholar
  46. 46.
    Liu Y, Cao Y, Sun S, Zhu J, Gao S, Pang J, et al. Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways. Int J Biochem Cell Biol. 2016;77(Pt A):141–54.PubMedGoogle Scholar
  47. 47.
    Gore B, Izikki M, Mercier O, Dewachter L, Fadel E, Humbert M, et al. Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension. PLoS One. 2014;9(6):e100310.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Namiki A, Brogi E, Kearney M, Kim EA, Wu T, Couffinhal T, et al. Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chem. 1995;270(52):31189–95.PubMedGoogle Scholar
  49. 49.
    Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447–54.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Voelkel NF, Gomez-Arroyo J. The role of vascular endothelial growth factor in pulmonary arterial hypertension. The angiogenesis paradox. Am J Respir Cell Mol Biol. 2014;51(4):474–84.PubMedGoogle Scholar
  51. 51.
    Jiang Y, Wang J, Tian H, Li G, Zhu H, Liu L, et al. Increased SUMO-1 expression in response to hypoxia: interaction with HIF-1alpha in hypoxic pulmonary hypertension. Int J Mol Med. 2015;36(1):271–81.PubMedGoogle Scholar
  52. 52.
    Liu J, Wang W, Wang L, Chen S, Tian B, Huang K, et al. IL-33 initiates vascular remodelling in hypoxic pulmonary hypertension by up-regulating HIF-1alpha and VEGF expression in vascular endothelial cells. EBioMedicine. 2018;33:196–210.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon G, Waltenberger J, et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 2001;15(2):427–38.PubMedGoogle Scholar
  54. 54.
    Nicolls MR, Mizuno S, Taraseviciene-Stewart L, Farkas L, Drake JI, Al Husseini A, et al. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis. Pulm Circ. 2012;2(4):434–42.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Christou H, Yoshida A, Arthur V, Morita T, Kourembanas S. Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol. 1998;18(6):768–76.PubMedGoogle Scholar
  56. 56.
    Tuder RM, Flook BE, Voelkel NF. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest. 1995;95(4):1798–807.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Partovian C, Adnot S, Raffestin B, Louzier V, Levame M, Mavier IM, et al. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol. 2000;23(6):762–71.PubMedGoogle Scholar
  58. 58.
    Louzier V, Raffestin B, Leroux A, Branellec D, Caillaud JM, Levame M, et al. Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2003;284(6):L926–37.PubMedGoogle Scholar
  59. 59.
    Liang S, Yu H, Chen X, Shen T, Cui Z, Si G, et al. PDGF-BB/KLF4/VEGF signaling axis in pulmonary artery endothelial cell angiogenesis. Cell Physiol Biochem. 2017;41(6):2333–49.PubMedGoogle Scholar
  60. 60.
    Fuks Z, Persaud RS, Alfieri A, McLoughlin M, Ehleiter D, Schwartz JL, et al. Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo. Cancer Res. 1994;54(10):2582–90.PubMedGoogle Scholar
  61. 61.
    Wieder R, Wang H, Shirke S, Wang Q, Menzel T, Feirt N, et al. Low level expression of basic FGF upregulates Bcl-2 and delays apoptosis, but high intracellular levels are required to induce transformation in NIH 3T3 cells. Growth Factors. 1997;15(1):41–60.PubMedGoogle Scholar
  62. 62.
    König A, Menzel T, Lynen S, Wrazel L, Rosén A, Al-Katib A, et al. Basic fibroblast growth factor (bFGF) upregulates the expression of bcl-2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis. Leukemia. 1997;11(2):258–65.PubMedGoogle Scholar
  63. 63.
    Izikki M, Guignabert C, Fadel E, Humbert M, Tu L, Zadigue P, et al. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest. 2009;119(3):512–23.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Tu L, Dewachter L, Gore B, Fadel E, Dartevelle P, Simonneau G, et al. Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension. Am J Respir Cell Mol Biol. 2011;45(2):311–22.PubMedGoogle Scholar
  65. 65.
    Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med. 2013;19(1):74–82.PubMedGoogle Scholar
  66. 66.
    Ambalavanan N, Novak ZE. Peptide growth factors in tracheal aspirates of mechanically ventilated preterm neonates. Pediatr Res. 2003;53(2):240–4.PubMedGoogle Scholar
  67. 67.
    Benisty JI, McLaughlin VV, Landzberg MJ, Rich JD, Newburger JW, Rich S, et al. Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest. 2004;126(4):1255–61.PubMedGoogle Scholar
  68. 68.
    Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol. 2009;297(6):L1013–32.PubMedGoogle Scholar
  69. 69.
    Conte C, Riant E, Toutain C, Pujol F, Arnal JF, Lenfant F, et al. FGF2 translationally induced by hypoxia is involved in negative and positive feedback loops with HIF-1alpha. PLoS One. 2008;3(8):e3078.PubMedPubMedCentralGoogle Scholar
  70. 70.
    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(6):H2528–34.PubMedGoogle Scholar
  71. 71.
    Tuchscherer HA, Vanderpool RR, Chesler NC. Pulmonary vascular remodeling in isolated mouse lungs: effects on pulsatile pressure-flow relationships. J Biomech. 2007;40(5):993–1001.PubMedGoogle Scholar
  72. 72.
    Chang YT, Tseng CN, Tannenberg P, Eriksson L, Yuan K, de Jesus Perez VA, et al. Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension. Cardiovasc Res. 2015;107(1):20–31.PubMedGoogle Scholar

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Authors and Affiliations

  • Kel Vin Woo
    • 1
    • 2
  • David M. Ornitz
    • 2
  • Gautam K. Singh
    • 1
    Email author
  1. 1.Department of PediatricsWashington University School of MedicineSt. LouisUSA
  2. 2.Department of Developmental BiologyWashington University School of MedicineSaint LouisUSA

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