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The sexual dimorphism associated with pulmonary hypertension corresponds to a fibrotic phenotype

Olga Rafikova, Ruslan Rafikov, Mary Louise Meadows, Archana Kangath, Danny Jonigk and Stephen M. Black
Pulmonary Circulation
Vol. 5, No. 1 (March 2015), pp. 184-197
DOI: 10.1086/679724
Stable URL:
Page Count: 14
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AbstractAlthough female predominance in the development of all types of pulmonary hypertension (PH) is well established, many clinical studies have confirmed that females have better prognosis and higher survival rate than males. There is no clear explanation of why sex influences the pathogenesis and progression of PH. Using a rat angioproliferative model of PH, which closely resembles the primary pathological changes observed in humans, we evaluated the role of sex in the development and progression of PH. Female rats had a more pronounced increase in medial thickness in the small pulmonary arteries. However, the infiltration of small pulmonary arteries by inflammatory cells was found only in male rats, and this corresponded to increased myeloperoxidase activity and abundant adventitial and medial fibrosis that were not present in female rats. Although the level of right ventricle (RV) peak systolic pressure was similar in both groups, the survival rate in male rats was significantly lower. Moreover, male rats presented with a more pronounced increase in RV thickness that correlated with diffuse RV fibrosis and significantly impaired right cardiac function. The reduction in fibrosis in female rats correlated with increased expression of caveolin-1 and reduced endothelial nitric oxide synthase–derived superoxide. We conclude that, in the pathogenesis of PH, female sex is associated with greater remodeling of the pulmonary arteries but greater survival. Conversely, in males, the development of pulmonary and cardiac fibrosis leads to early and severe RV failure, and this may be an important reason for the lower survival rate among males.

Notes and References

This item contains 60 references.

  • 1.
    ['1. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet 2003;361:1533–1544.']
  • 2.
    ['2. Townsend EA, Miller VM, Prakash YS. Sex differences and sex steroids in lung health and disease. Endocr Rev 2012;33:1–47.']
  • 3.
    ['3. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216–223.']
  • 4.
    ['4. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL registry. Chest 2010;137:376–387.']
  • 5.
    ['5. Pugh ME, Hemnes AR. Development of pulmonary arterial hypertension in women: interplay of sex hormones and pulmonary vascular disease. Womens Health (Lond Engl) 2010;6:285–296.']
  • 6.
    ['6. Tofovic SP. Estrogens and development of pulmonary hypertension: interaction of estradiol metabolism and pulmonary vascular disease. J Cardiovasc Pharmacol 2010;56:696–708.']
  • 7.
    ['7. Sharma S, Sun X, Kumar S, et al. Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase I. Free Radic Biol Med 2012;53:216–229.']
  • 8.
    ['8. de Jesus Perez VA. Making sense of the estrogen paradox in pulmonary arterial hypertension. Am J Resp Crit Care Med 2011;184:629–630.']
  • 9.
    ['9. Earley S, Resta TC. Estradiol attenuates hypoxia-induced pulmonary endothelin-1 gene expression. Am J Physiol 2002;283:L86–L93.']
  • 10.
    ['10. Lahm T, Crisostomo PR, Markel TA, et al. The effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction: potential new clinical implications for an old hormone. Crit Care Med 2008;36:2174–2183.']
  • 11.
    ['11. Lahm T, Crisostomo PR, Markel TA, et al. Exogenous estrogen rapidly attenuates pulmonary artery vasoreactivity and acute hypoxic pulmonary vasoconstriction. Shock 2008;30:660–667.']
  • 12.
    ['12. Sherman TS, Chambliss KL, Gibson LL, et al. Estrogen acutely activates prostacyclin synthesis in ovine fetal pulmonary artery endothelium. Am J Resp Cell Mol Biol 2002;26:610–616.']
  • 13.
    ['13. Jesmin S, Mowa CN, Sultana SN, et al. Estrogen receptor alpha and beta are both involved in the cerebral VEGF/Akt/NO pathway and cerebral angiogenesis in female mice. Biomed Res 2010;31:337–346.']
  • 14.
    ['14. Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci USA 2000;97:10972–10977.']
  • 15.
    ['15. Dempsie Y, Nilsen M, White K, et al. Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females. Respir Res 2011;12:159.']
  • 16.
    ['16. Oviedo PJ, Sobrino A, Laguna-Fernandez A, et al. Estradiol induces endothelial cell migration and proliferation through estrogen receptor-enhanced RhoA/ROCK pathway. Mol Cell Endocrinol 2011;335:96–103.']
  • 17.
    ['17. Cleuren AC, van Oerle R, Reitsma PH, Spronk HM, van Vlijmen BJ. Long-term estrogen treatment of mice with a prothrombotic phenotype induces sustained increases in thrombin generation without affecting tissue fibrin deposition. J Thromb Haemost 2012;10:2392–2394.']
  • 18.
    ['18. DeLoughery TG. Estrogen and thrombosis: controversies and common sense. Rev Endocr Metab Disord 2011;12:77–84.']
  • 19.
    ['19. Gouva L, Tsatsoulis A. The role of estrogens in cardiovascular disease in the aftermath of clinical trials. Hormones (Athens) 2004;3:171–183.']
  • 20.
    ['20. Escribano-Subias P, Blanco I, Lopez-Meseguer M, et al. Survival in pulmonary hypertension in Spain: insights from the Spanish registry. Eur Respir J 2012;40:596–603.']
  • 21.
    ['21. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010;122:164–172.']
  • 22.
    ['22. Humbert M, Sitbon O, Yaici A, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010;36:549–555.']
  • 23.
    ['23. Lee WT, Ling Y, Sheares KK, Pepke-Zaba J, Peacock AJ, Johnson MK. Predicting survival in pulmonary arterial hypertension in the UK. Eur Respir J 2012;40:604–611.']
  • 24.
    ['24. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343–349.']
  • 25.
    ['25. Bhupathy P, Haines CD, Leinwand LA. Influence of sex hormones and phytoestrogens on heart disease in men and women. Womens Health (Lond Engl) 2010;6:77–95.']
  • 26.
    ['26. Kadokami T, McTiernan CF, Kubota T, Frye CS, Feldman AM. Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. J Clin Invest 2000;106:589–597.']
  • 27.
    ['27. Witt H, Schubert C, Jaekel J, et al. Sex-specific pathways in early cardiac response to pressure overload in mice. J Mol Med (Berl) 2008;86:1013–1024.']
  • 28.
    ['28. Petre RE, Quaile MP, Rossman EI, et al. Sex-based differences in myocardial contractile reserve. Am J Physiol Regul Integr Comp Physiol 2007;292:R810–R818.']
  • 29.
    ['29. Abe K, Toba M, Alzoubi A, et al. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 2010;121:2747–2754.']
  • 30.
    ['30. Rafikova O, Rafikov R, Kumar S, et al. Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonary hypertension. Free Radic Biol Med 2013;56:28–43.']
  • 31.
    ['31. van Suylen RJ, Smits JF, Daemen MJ. Pulmonary artery remodeling differs in hypoxia- and monocrotaline-induced pulmonary hypertension. Am J Resp Crit Care Med 1998;157:1423–1428.']
  • 32.
    ['32. Jacoby JJ, Kalinowski A, Liu MG, et al. Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci USA 2003;100:12929–12934.']
  • 33.
    ['33. Sud N, Sharma S, Wiseman DA, et al. Nitric oxide and superoxide generation from endothelial NOS: modulation by HSP90. Am J Physiol 2007;293:L1444–L1453.']
  • 34.
    ['34. Sharma S, Sud N, Wiseman DA, et al. Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension. Am J Physiol 2008;294:L46–L56.']
  • 35.
    ['35. Yared K, Noseworthy P, Weyman AE, McCabe E, Picard MH, Baggish AL. Pulmonary artery acceleration time provides an accurate estimate of systolic pulmonary arterial pressure during transthoracic echocardiography. J Am Soc Echocardiogr 2011;24:687–692.']
  • 36.
    ['36. Palevsky HI, Schloo BL, Pietra GG, et al. Primary pulmonary hypertension: vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation 1989;80:1207–1221.']
  • 37.
    ['37. Strauss BH, Rabinovitch M. Adventitial fibroblasts: defining a role in vessel wall remodeling. Am J Respir Cell Mol Biol 2000;22:1–3.']
  • 38.
    ['38. Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda) 2006;21:134–145.']
  • 39.
    ['39. Chen F, Barman S, Yu Y, et al. Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med 2014;73:201–213.']
  • 40.
    ['40. Walters DM, Cho HY, Kleeberger SR. Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2. Antioxid Redox Signal 2008;10:321–332.']
  • 41.
    ['41. Kinnula VL, Fattman CL, Tan RJ, Oury TD. Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. Am J Respir Crit Care Med 2005;172:417–422.']
  • 42.
    ['42. Aragno M, Mastrocola R, Alloatti G, et al. Oxidative stress triggers cardiac fibrosis in the heart of diabetic rats. Endocrinology 2008;149:380–388.']
  • 43.
    ['43. Wetzel RC, Sylvester JT. Gender differences in hypoxic vascular response of isolated sheep lungs. J Appl Physiol Respir Environ Exerc Physiol 1983;55:100–104.']
  • 44.
    ['44. Jones RD, English KM, Pugh PJ, Morice AH, Jones TH, Channer KS. Pulmonary vasodilatory action of testosterone: evidence of a calcium antagonistic action. J Cardiovasc Pharmacol 2002;39:814–823.']
  • 45.
    ['45. Price LC, Wort SJ, Perros F, et al. Inflammation in pulmonary arterial hypertension. Chest 2012;141:210–221.']
  • 46.
    ['46. Hall S, Brogan P, Haworth SG, Klein N. Contribution of inflammation to the pathology of idiopathic pulmonary arterial hypertension in children. Thorax 2009;64:778–783.']
  • 47.
    ['47. Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Col Cardiol 2009;54:S10–S19.']
  • 48.
    ['48. Perros F, Dorfmuller P, Souza R, et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J 2007;29:462–468.']
  • 49.
    ['49. Ulrich S, Nicolls MR, Taraseviciene L, Speich R, Voelkel N. Increased regulatory and decreased CD8+ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension. Respiration 2008;75:272–80.']
  • 50.
    ['50. Karakas M, Koenig W. Myeloperoxidase production by macrophage and risk of atherosclerosis. Curr Atheroscler Rep 2012;14:277–283.']
  • 51.
    ['51. Loria V, Dato I, Graziani F, Biasucci LM. Myeloperoxidase: a new biomarker of inflammation in ischemic heart disease and acute coronary syndromes. Mediators Inflamm 2008;2008:135625.']
  • 52.
    ['52. Friedrichs K, Baldus S, Klinke A. Fibrosis in atrial fibrillation: role of reactive species and MPO. Front Physiol 2012;3:214.']
  • 53.
    ['53. Rafikov R, Rafikova O, Aggarwal S, et al. Asymmetric dimethylarginine induces endothelial nitric oxide synthase mitochondrial redistribution through the nitration-mediated activation of Akt1. J Biol Chem 2013;288:6212–6226.']
  • 54.
    ['54. Stenmark KR, Davie NJ, Reeves JT, Frid MG. Hypoxia, leukocytes, and the pulmonary circulation. J Appl Physiol Respir Environ Exerc Physiol 2005;98:715–721.']
  • 55.
    ['55. Karuppiah K, Druhan LJ, Chen CA, et al. Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism. Am J Physiol Heart Circ Physiol 2011;301:H903–H911.']
  • 56.
    ['56. Zhao YY, Liu Y, Stan RV, et al. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci USA 2002;99:11375–11380.']
  • 57.
    ['57. Hemnes AR, Maynard KB, Champion HC, et al. Testosterone negatively regulates right ventricular load stress responses in mice. Pulm Circ 2012;2:352–358.']
  • 58.
    ['58. Li Y, Kishimoto I, Saito Y, et al. Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. Endocrinology 2004;145:951–958.']
  • 59.
    ['59. Voltz JW, Card JW, Carey MA, et al. Male sex hormones exacerbate lung function impairment after bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 2008;39:45–52.']
  • 60.
    ['60. Bogaard HJ, Natarajan R, Henderson SC, et al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 2009;120:1951–1960.']