European Cytokine Network

, Volume 28, Issue 1, pp 1–7 | Cite as

Pulmonary artery hypertension: pertinent vasomotorial cytokines

  • Shi-Min Yuan


Pulmonary artery hypertension is a syndrome that shows similar clinical and pathophysiological features characterized by elevated pulmonary arterial pressure and resistance. There have been a series of hypotheses trying to describe the development of pulmonary artery hypertension; however, none of them perfectly explains its pathogenesis. To highlight the pathogenesis, novel vasomotorial cytokines including hypoxia-inducible factor-1α, endothelin-1, urotensin II, Krüppel-like factor 4, calcitonin gene-related peptide, angiopoietins and serotonin closely related to pulmonary artery hypertension are discussed. The development of the new agents relating to these cytokines may improve the relevant treatment strategies.

Key words

cytokines pathogenesis pulmonary hypertension 


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  1. 1.
    Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2012; 122: 4306–13.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 2010; 121: 2045–66.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinicalimportance, and management of right ventricular failure. Circulation 2008; 117: 1717–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Neubauer S. The failing heart–an engine out of fuel. N Engl J Med 2007; 356: 1140–51.CrossRefPubMedGoogle Scholar
  5. 5.
    Drake JI, Gomez-Arroyo J, Dumur CI, et al. Chronic carvedilol treatment partially reverses the right ventricular failure transcriptional profile in experimental pulmonary hypertension. Physiol Genomics 2013; 45: 449–61.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bogaard HJ, Natarajan R, Mizuno S, et al. Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med 2010; 182: 652–60.CrossRefPubMedGoogle Scholar
  7. 7.
    Wang L, Zhou Y, Li M, Zhu Y. Expression of hypoxiainducible factor-1α, endothelin-1 and adrenomedullin in newborn rats with hypoxia-induced pulmonary hypertension. Exp Ther Med 2014; 8: 335–9.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Pang YS, Chen MW, Han YL, Zeng M. Pulmonary arterial smooth muscle cell and pulmonary artery hypertension. J Appl Chin Pediatr 2009; 24: 1046–8.Google Scholar
  9. 9.
    Nakanishi K, Osada H, Uenoyama M, et al. Expressions of adrenomedullin mRNA and protein in rats with hypobaric hypoxiainduced pulmonary hypertension. Am J Physiol Heart Circ Physiol 2004; 286: H2159–68.CrossRefPubMedGoogle Scholar
  10. 10.
    Eul B, Rose F, Krick S, et al. Impact of HIF-1α and HIF-2α on proliferation and migration of human pulmonary artery fibroblasts in hypoxia. FASEB J 2006; 20: 163–5.PubMedGoogle Scholar
  11. 11.
    Ball MK, Waypa GB, Mungai PT, et al. Regulation of hypoxiainduced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. Am J Respir Crit Care Med 2014; 189: 314–24.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kim YM, Barnes EA, Alvira CM, Ying L, Reddy S, Cornfield DN. Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation. Circ Res 2013; 112: 1230–3.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Pinto-Sietsma SJ, Paul M. A role for endothelin in the pathogenesis of hypertension: fact or fiction? Kidney Int Suppl 1998; 67: S115–121.CrossRefPubMedGoogle Scholar
  14. 14.
    Rosanò L, Spinella F, Bagnato A. Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2013; 13: 637–51.CrossRefPubMedGoogle Scholar
  15. 15.
    Li M, Liu Y, Jin F, et al. Endothelin-1 induces hypoxia inducible factor 1α expression in pulmonary artery smooth muscle cells. FEBS Lett 2012; 586: 3888–93. doi: 10.1016/j.febslet.2012.08.036.CrossRefPubMedGoogle Scholar
  16. [16].
    Satwiko MG, Ikeda K, Nakayama K, et al. Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension. Biochem Biophys Res Commun 2015; 465: 356–62. doi: 10.1016/j.bbrc.2015.08.002.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu C, Chen J, Gao Y, Deng B, Liu K. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev 2013; 2: CD004434.Google Scholar
  18. 18.
    Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001; 120: 1562–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 2008; 31: 407–15.CrossRefPubMedGoogle Scholar
  20. 20.
    Ames RS, Sarau HM, Chambers JK, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999; 401: 282–6.CrossRefPubMedGoogle Scholar
  21. 21.
    [No authors listed]. Guide to Receptors and Channels (GRAC), 4th Edition. Br J Pharmacol 2009; 158: S1-254.Google Scholar
  22. 22.
    Zhang Y, Li J, Cao J, et al. Effect of chronic hypoxia on contents of urotensin II and its functional receptors in rat myocardium. Heart Vessels 2002; 16: 64–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Qi J, Du J, Tang X, Li J, Wei B, Tang C. The upregulation of endothelial nitric oxide synthase and UTII is associated with PAH and vascular diseases in rats produced by aortocaval shunting. Heart Vessels 2004; 19: 81–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Chen YH, Zhao MW, Yao WZ, Pang YZ, Tang CS. The signal transduction pathway in the proliferation of airway smooth muscle cells induced by urotensin II. Chin Med J (Engl) 2004; 117: 37–41.Google Scholar
  25. 25.
    Zhang WX, Liang YF, Wang XM, et al. Urotensin upregulates transforming growth factor-α1 expression of asthma airway through ERK-dependent pathway. Mol Cell Biochem 2012; 364: 291–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Douglas SA, Sulpizio AC, Piercy V, et al. Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey. Br J Pharmacol 2000; 131: 1262–74.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hay DW, Luttmann MA, Douglas SA. Human urotensin-II is a potent spasmogen of primate airway smooth muscle. Br J Pharmacol 2000; 131: 10–2.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    MacLean MR, Alexander D, Stirrat A, et al. Contractile responses to human urotensin-II in rat and human pulmonary arteries: effect of endothelial factors and chronic hypoxia in the rat. Br J Pharmacol 2000; 130: 201–4.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ross B, McKendy K, Giaid A. Role of urotensin II in health and disease. Am J Physiol Regul Integr Comp Physiol 2010; 298: R1156–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Watanabe T, Arita S, Shiraishi Y, et al. Human urotensin II promotes hypertension and atherosclerotic cardiovascular diseases. Curr Med Chem 2009; 16: 550–63.CrossRefPubMedGoogle Scholar
  31. 31.
    Djordjevic T, Görlach A. Urotensin-II in the lung: a matter for vascular remodelling and pulmonary hypertension? Thromb Haemost 2007; 98: 952–62, Scholar
  32. 32.
    Djordjevic T, Bel Aiba RS, Bonello S, Pfeilschifter J, Hess J, Görlach A. Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells. Arterioscler Thromb Vasc Biol 2005; 25: 519–25.CrossRefPubMedGoogle Scholar
  33. 33.
    Rong X, Wu HP, Qiu HX, et al. Expression and role of urotensin II on the lung of patients with pulmonary hypertension with congenital heart disease. Zhonghua Er Ke Za Zhi 2012; 50: 689–91.PubMedGoogle Scholar
  34. 34.
    Onat AM, Pehlivan Y, Turkbeyler IH, et al. Urotensin inhibition with palosuran could be a promising alternative in pulmonary arterial hypertension. Inflammation 2013; 36: 405–12.CrossRefPubMedGoogle Scholar
  35. 35.
    Behm DJ, Aiyar NV, Olzinski AR, et al. GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo. Br J Pharmacol 2010; 161: 207–28.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hamik A, Lin Z, Kumar A, et al. Kruppel-like factor 4 regulates endothelial inflammation. J Biol Chem 2007; 282: 13769–79.CrossRefPubMedGoogle Scholar
  37. 37.
    Shatat MA, Tian H, Zhang R, et al. Endothelial Krüppel-like factor 4 modulates pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2014; 50: 647–53.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Shatat MA, Peachey J, Hamik A, et al. Krüppel-like factor 4 modulates pulmonary arterial endothelial cells modulates smooth muscle cell phenotype. Am J Respir Cell Mol Biol 2016; 193: A2222, Scholar
  39. 39.
    Tugal D, Jain MK, Simon DI. Endothelial KLF4: crippling vascular injury? J Am Heart Assoc 2014; 3: e000769.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Li XW, Du J, Li YJ. The effect of calcitonin gene-related peptide on collagen accumulation in pulmonary arteries of rats with hypoxic pulmonary arterial hypertension. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2013; 29: 182–6192.PubMedGoogle Scholar
  41. 41.
    Bivalacqua TJ, Hyman AL, Kadowitz PJ, Paolocci N, Kass DA, Champion HC. Role of calcitonin gene-related peptide (CGRP) in chronic hypoxia-induced pulmonary hypertension in the mouse. Influence of gene transfer in vivo. Regul Pept 2002; 108: 129–33.PubMedGoogle Scholar
  42. 42.
    Ghatta S, Nimmagadda D. Calcitonin gene-related peptide: understanding its role. Indian J Pharmacol 2004; 36: 277–83.Google Scholar
  43. 43.
    Li XW, Hu CP, Wu WH, Zhang WF, Zou XZ, Li YJ. Inhibitory effect of calcitonin gene-related peptide on hypoxia-induced rat pulmonary artery smooth muscle cells proliferation: role of ERK1/2 and p27. Eur J Pharmacol 2012; 679: 117–26.CrossRefPubMedGoogle Scholar
  44. 44.
    Keith IM, Tjen-A-Looi S, Kraiczi H, Ekman R. Three-week neonatal hypoxia reduces blood CGRP and causes persistent pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol 2000; 279: H1571–8.PubMedGoogle Scholar
  45. 45.
    Bartosik I, Eskilsson J, Ekman R, Akesson A, Scheja A. Correlation between plasma concentrations of calcitonin gene related peptide and pulmonary pressure in patients with systemic sclerosis. Ann Rheum Dis 2002; 61: 261–3.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Yamamoto A, Takahashi H, Kojima Y, et al. Downregulation of angiopoietin-1 and Tie2 in chronic hypoxic pulmonary hypertension. Respiration 2008; 75: 328–38.CrossRefPubMedGoogle Scholar
  47. 47.
    Zhao YD, Campbell AI, Robb M, Ng D, Stewart DJ. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res 2003; 92: 984–91.CrossRefPubMedGoogle Scholar
  48. 48.
    Rudge JS, Thurston G, Yancopoulos GD. Angiopoietin-1 and pulmonary hypertension: cause or cure? Circ Res 2003; 92: 947–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Karapinar H, Esen O, Emiroğlu Y, et al. Serum levels of angiopoietin-1 in patients with pulmonary hypertension due to mitral stenosis. Heart Vessels 2011; 26: 536–41.CrossRefPubMedGoogle Scholar
  50. 50.
    Kümpers P, Nickel N, Lukasz A, et al. Circulating angiopoietins in idiopathic pulmonary arterial hypertension. Eur Heart J 2010; 31: 2291–300.CrossRefPubMedGoogle Scholar
  51. 51.
    Dewachter L, Adnot S, Fadel E, et al. Angiopoietin/Tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension. Am J Respir Crit Care Med 2006; 174: 1025–33.CrossRefPubMedGoogle Scholar
  52. 52.
    Li BB, Jiang Z. Role of serotonin in proliferation of pulmonary arterial smooth muscle cells and remodeling of pulmonary vasculature. Int J Anesth Resus 2007; 28: 441–4.Google Scholar
  53. 53.
    Dempsie Y, MacLean MR. Pulmonary hypertension: therapeutic targets within the serotonin system. Br J Pharmacol 2008; 155: 455–62.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Morecroft I, Loughlin L, Nilsen M, et al. Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries. J Pharmacol Exp Ther 2005; 313: 539–48.CrossRefPubMedGoogle Scholar
  55. 55.
    Sullivan CC, Du L, Chu D, et al. Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci U S A 2003; 100: 12331–6.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Kaumann AJ, Levy FO. 5-hydroxytryptamine receptors in the human cardiovascular system. Pharmacol Ther 2006; 111: 674–706.CrossRefPubMedGoogle Scholar
  57. 57.
    Wang JX, Tang FK, Xiao J, et al. Expression and distribution of 5-HTlB receptors in lung tissue in rats with hypoxic pulmonary hypertension. Chin J Pathophysiol 2010; 26: 1579–83.Google Scholar
  58. 58.
    Fanburg BL, Lee SL. A new role for an old molecule: serotonin as a mitogen. Am J Physiol 1997; 272: L795–806.PubMedGoogle Scholar
  59. 59.
    Eddahibi S, Fabre V, Boni C, et al. Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of serotonin. Circ Res 1999; 84: 329–36.CrossRefPubMedGoogle Scholar

Copyright information

© John Libbey Eurotext 2017

Authors and Affiliations

  1. 1.Department of Cardiothoracic Surgery, The First Hospital of Putian, Teaching HospitalFujian Medical UniversityPutian, Fujian ProvincePeople’s Republic of China

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