Pathobiology of pulmonary arterial hypertension: Understanding the roads less travelled

European Respiratory Review

Volumn 26, Issue 146, 2017, Pages

  Hemnes, Anna R ^a   Humbert, Marc ^b,c  

^a VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^b UNIVERSITÉ PARIS SACLAY   (France)

^c BICÊTRE HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

BONE MORPHOGENETIC PROTEIN RECEPTOR 2; CYTOCHROME P450 1A1; CYTOCHROME P450 1B1; ESTROGEN; FIBROBLAST GROWTH FACTOR 2; HIGH MOBILITY GROUP A PROTEIN; HIGH MOBILITY GROUP AT PROTEIN; IMATINIB; INTERLEUKIN 1BETA; INTERLEUKIN 6; MICRORNA; MICRORNA 130; MICRORNA 301; PLATELET DERIVED GROWTH FACTOR; POTASSIUM CHANNEL KV1.5; SORAFENIB; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR TAZ; TRANSCRIPTION FACTOR YAP; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG; ANTIHYPERTENSIVE AGENT;

ARTERIAL STIFFNESS; ARTERIAL WALL THICKNESS; BMPR2 GENE; CELL DIFFERENTIATION; CELL MIGRATION; CELL PROLIFERATION; CELL TRANSFORMATION; DISEASE SEVERITY; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; ENDOTHELIAL MESENCHYMAL TRANSITION; GENE; GENE EXPRESSION REGULATION; HUMAN; IMMUNE DEFICIENCY; IRON DEPLETION; IRON HOMEOSTASIS; KCNK3 GENE; LOSS OF FUNCTION MUTATION; MEMBRANE STEADY POTENTIAL; PATHOGENESIS; PERICYTE; PHASE 3 CLINICAL TRIAL (TOPIC); POSITIVE FEEDBACK; PROTEIN DNA BINDING; PULMONARY HYPERTENSION; REVIEW; SMOOTH MUSCLE CELL; TASK 1 GENE; TGF BETA SIGNALING; TRANSCRIPTION INITIATION; TREATMENT RESPONSE; UPREGULATION; VASCULAR REMODELING; ANIMAL; ARTERIAL PRESSURE; COMBINATION DRUG THERAPY; DISEASE EXACERBATION; DRUG EFFECT; EPITHELIAL MESENCHYMAL TRANSITION; METABOLISM; PATHOLOGY; PATHOPHYSIOLOGY; PULMONARY ARTERY; RISK FACTOR; SIGNAL TRANSDUCTION;

ANIMALS; ANTIHYPERTENSIVE AGENTS; ARTERIAL PRESSURE; DISEASE PROGRESSION; DRUG THERAPY, COMBINATION; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; HYPERTENSION, PULMONARY; PULMONARY ARTERY; RISK FACTORS; SIGNAL TRANSDUCTION; VASCULAR REMODELING; VASCULAR STIFFNESS;

EID: 85039728109     PISSN: 09059180     EISSN: 16000617     Source Type: Journal    
DOI: 10.1183/16000617.0093-2017     Document Type: Review

References (106)

1. Humbert M, Lau EM, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 2014; 130: 2189–2208.
2. Galiè N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J 2010; 31: 2080–2086.
3. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th Edn. New York, Garland Science, 2002; p. 1616.
4. Lilly B. We have contact: endothelial cell-smooth muscle cell interactions. Physiology 2014; 29: 234–241.
5. Gao Y, Chen T, Raj JU. Endothelial and smooth muscle cell interactions in the pathobiology of pulmonary hypertension. Am J Respir Cell Mol Biol 2016; 54: 451–460.
6. Metz RP, Patterson JL, Wilson E. Vascular smooth muscle cells: isolation, culture, and characterization. Methods Mol Biol 2012; 843: 169–176.
7. de Jesus Perez VA. Molecular pathogenesis and current pathology of pulmonary hypertension. Heart Fail Rev 2016; 21: 239–257.
8. Tuder R, Archer SL, Dorfmuller P. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 2013; 62: Suppl 25, D4–D12.
9. Bertero T, Cottrill KA, Lu Y, et al. Matrix remodeling promotes pulmonary hypertension through feedback mechanoactivation of the YAP/TAZ-miR-130/301 circuit. Cell Rep 2015; 13: 1016–1032.
10. Bertero T, Oldham WM, Cottrill KA, et al. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest 2016; 126: 3313–3335.
11. Hopper RK, Moonen JR, Diebold I, et al. In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to-mesenchymal transition via HMGA1 and its target slug. Circulation 2016; 133: 1783–1794.
12. Stenmark KR, Frid M, Perros F. Endothelial-to-mesenchymal transition: an evolving paradigm and a promising therapeutic target in PAH. Circulation 2016; 133: 1734–1737.
13. Ranchoux B, Antigny F, Rucker-Martin C, et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 2015; 131: 1006–1018.
14. Chien S. Effects of disturbed flow on endothelial cells. Ann Biomed Eng 2008; 36: 554–562.
15. Li M, Scott DE, Shandas R, et al. High pulsatility flow induces adhesion molecule and cytokine mRNA expression in distal pulmonary artery endothelial cells. Ann Biomed Eng 2009; 37: 1082–1092.
16. Elliott WH, Tan Y, Li M, et al. High pulsatility flow promotes vascular fibrosis by triggering endothelial endmt and fibroblast activation. Cell Mol Bioeng 2015; 8: 285–295.
17. Cooley BC, Nevado J, Mellad J, et al. TGF-beta signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci Transl Med 2014; 6: 227ra34.
18. Kumarswamy R, Volkmann I, Jazbutyte V, et al. Transforming growth factor-beta-induced endothelial-tomesenchymal transition is partly mediated by microRNA-21. Arterioscler Thromb Vasc Biol 2012; 32: 361–369.
19. Ricard N, Tu L, Le Hiress M, et al. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation 2014; 129: 1586–1597.
20. Geevarghese A, Herman IM. Pericyte-endothelial cross-talk: implications and opportunities for advanced cellular therapies. Transl Res 2014; 163: 296–306.
21. Guignabert C, Bailly S, Humbert M. Restoring BMPRII functions in pulmonary arterial hypertension: opportunities, challenges and limitations. Expert Opin Ther Targets 2017; 21: 181–190.
22. Fessel JP, Loyd JE, Austin ED. The genetics of pulmonary arterial hypertension in the post-BMPR2 era. Pulm Circ 2011; 1: 305–319.
23. Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002; 105: 1672–1678.
24. Rothman AM, Arnold ND, Pickworth JA, et al. MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. J Clin Invest 2016; 126: 2495–2508.
25. Larkin EK, Newman JH, Austin ED, et al. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 892–896.
26. Song Y, Jones JE, Beppu H, et al. Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation 2005; 112: 553–562.
27. Hurst LA, Dunmore BJ, Long L, et al. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nat Commun 2017; 8: 14079.
28. Savai R, Al-Tamari HM, Sedding D, et al. Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension. Nat Med 2014; 20: 1289–1300.
29. Spiekerkoetter E, Tian X, Cai J, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest 2013; 123: 3600–3613.
30. Long L, Yang X, Southwood M, et al. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circ Res 2013; 112: 1159–1170.
31. Long L, Ormiston ML, Yang X, et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 2015; 21: 777–785.
32. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67: 737–744.
33. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005; 115: 2811–2821.
34. Humbert M, Monti G, Fartoukh M, et al. Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur Respir J 1998; 11: 554–559.
35. Perros F, Montani D, Dorfmüller P, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2008; 178: 81–88.
36. Izikki M, Guignabert C, Fadel E, et al. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 2009; 119: 512–523.
37. Benisty JI, McLaughlin VV, Landzberg MJ, et al. Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 2004; 126: 1255–1261.
38. Tu L, Dewachter L, Gore B, et al. Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension. Am J Respir Cell Mol Biol 2011; 45: 311–322.
39. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 2013; 127: 1128–1138.
40. Humbert M. Impression, sunset. Circulation 2013; 127: 1098–1100.
41. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005; 353: 1412–1413.
42. Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 2010; 182: 1171–1177.
43. Patterson KC, Weissmann A, Ahmadi T, et al. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med 2006; 145: 152–153.
44. Souza R, Sitbon O, Parent F, et al. Long term imatinib treatment in pulmonary arterial hypertension. Thorax 2006; 61: 736.
45. Simonneau G, Hoeper MM, McLaughlin V, et al. Future perspectives in pulmonary arterial hypertension. Eur Respir Rev 2016; 25: 381–389.
46. Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009; 54: Suppl 1, S10–S19.
47. Voelkel NF, Gomez-Arroyo J, Abbate A, et al. Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J 2012; 40: 1555–1565.
48. Huertas A, Perros F, Tu L, et al. Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: a complex interplay. Circulation 2014; 129: 1332–1340.
49. Kherbeck N, Tamby MC, Bussone G, et al. The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension. Clin Rev Allerg Immunol 2013; 44: 31–38.
50. Rabinovitch M, Guignabert C, Humbert M, et al. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014; 115: 165–175.
51. Perros F, Dorfmüller P, Montani D, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 185: 311–321.
52. Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995; 151: 1628–1631.
53. Sanchez O, Marcos E, Perros F, et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2007; 176: 1041–1047.
54. Speich R, Jenni R, Opravil M, et al. Primary pulmonary hypertension in HIV infection. Chest 1991; 100: 1268–1271.
55. Radstake TR, van Bon L, Broen J, et al. Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFβ expression. PLoS One 2009; 4: e5981.
56. Bonelli M, Savitskaya A, Steiner CW, et al. Phenotypic and functional analysis of CD4+ CD25- Foxp3+ T cells in patients with systemic lupus erythematosus. J Immunol 2009; 182: 1689–1695.
57. Cohen-Kaminsky S, Hautefort A, Price L, et al. Inflammation in pulmonary hypertension: what we know and what we could logically and safely target first. Drug Discov Today 2014; 19: 1251–1256.
58. Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum 2008; 58: 521–531.
59. Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013; 369: 351–361.
60. Navas Tejedor P, Tenorio Castano J, Palomino Doza J, et al. An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension. Clin Genet 2017; 91: 453–457.
61. Brayden JE. Potassium channels in vascular smooth muscle. Clin Exp Pharmacol Physiol 1996; 23: 1069–1076.
62. Girerd B, Perros F, Antigny F, et al. KCNK3: new gene target for pulmonary hypertension? Expert Rev Respir Med 2014; 8: 385–387.
63. Huang X, Jan LY. Targeting potassium channels in cancer. J Cell Biol 2014; 206: 151–162.
64. Antigny F, Hautefort A, Meloche J, et al. Potassium channel subfamily K member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension. Circulation 2016; 133: 1371–1385.
65. Yuan XJ, Wang J, Juhaszova M, et al. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 1998; 351: 726–727.
66. Bonnet S, Michelakis ED, Porter CJ, et al. An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 2006; 113: 2630–2641.
67. Pozeg ZI, Michelakis ED, McMurtry MS, et al. In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 2003; 107: 2037–2044.
68. Fessel JP, Chen X, Frump A, et al. Interaction between bone morphogenetic protein receptor type 2 and estrogenic compounds in pulmonary arterial hypertension. Pulm Circ 2013; 3: 564–577.
69. Tofovic SP, Salah EM, Mady HH, et al. Estradiol metabolites attenuate monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2005; 46: 430–437.
70. Tofovic SP, Zhang X, Jackson EK, et al. 2-Methoxyestradiol mediates the protective effects of estradiol in monocrotaline-induced pulmonary hypertension. Vascul Pharmacol 2006; 45: 358–367.
71. Austin ED, Cogan JD, West JD, et al. Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J 2009; 34: 1093–1099.
72. Chen X, Talati M, Fessel JP, et al. Estrogen metabolite 16alpha-hydroxyestrone exacerbates bone morphogenetic protein receptor type ii-associated pulmonary arterial hypertension through microrna-29-mediated modulation of cellular metabolism. Circulation 2016; 133: 82–97.
73. Pugh ME, Hemnes AR. Metabolic and hormonal derangements in pulmonary hypertension: from mouse to man. Int J Clin Pract Suppl 2010; 268: 5–13.
74. Lahm T, Albrecht M, Fisher AJ, et al. 17beta-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects. Am J Respir Crit Care Med 2012; 185: 965–980.
75. Massart J, Sjogren RJO, Lundell LS, et al. Altered miR-29 expression in type 2 diabetes influences glucose and lipid metabolism in skeletal muscle. Diabetes 2017; 66: 1807–1818.
76. Rhodes CJ, Howard LS, Busbridge M, et al. Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: clinical prevalence, outcomes, and mechanistic insights. J Am Coll Cardiol 2011; 58: 300–309.
77. Ruiter G, Lankhorst S, Boonstra A, et al. Iron deficiency is common in idiopathic pulmonary arterial hypertension. Eur Respir J 2011; 37: 1386–1391.
78. van Empel VP, Lee J, Williams TJ, et al. Iron deficiency in patients with idiopathic pulmonary arterial hypertension. Heart Lung Circ 2014; 23: 287–292.
79. Smith TG, Balanos GM, Croft QP, et al. The increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J Physiol (Lond) 2008; 586: 5999–6005.
80. Smith TG, Talbot NP, Privat C, et al. Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials. J Am Med Assoc 2009; 302: 1444–1450.
81. Cotroneo E, Ashek A, Wang L, et al. Iron homeostasis and pulmonary hypertension: iron deficiency leads to pulmonary vascular remodeling in the rat. Circ Res 2015; 116: 1680–1690.
82. Meloche J, Pflieger A, Vaillancourt M, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation 2014; 129: 786–797.
83. Paulin R, Courboulin A, Meloche J, et al. Signal transducers and activators of transcription-3/pim1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension. Circulation 2011; 123: 1205–1215.
84. Li X, Zhang X, Leathers R, et al. Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat Med 2009; 15: 1289–1297.
85. Archer SL, Marsboom G, Kim GH, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 2010; 121: 2661–2671.
86. Chelladurai P, Seeger W, Pullamsetti SS. Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives. Eur Respir Rev 2016; 25: 135–140.
87. Zhou G, Chen T, Raj JU. MicroRNAs in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2015; 52: 139–151.
88. Meloche J, Potus F, Vaillancourt M, et al. Bromodomain-containing protein 4: the epigenetic origin of pulmonary arterial hypertension. Circ Res 2015; 117: 525–535.
89. Federici C, Drake KM, Rigelsky CM, et al. Increased mutagen sensitivity and DNA damage in pulmonary arterial hypertension. Am J Respir Crit Care Med 2015; 192: 219–228.
90. 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: 474–484.
91. Chan SY, Rubin LJ. Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice. Eur Respir Rev 2017; 26: 170094.
92. Hunter KS, Lammers SR, Shandas R. Pulmonary vascular stiffness: measurement, modeling, and implications in normal and hypertensive pulmonary circulations. Compr Physiol 2011; 1: 1413–1435.
93. Chen Q, Zhang H, Liu Y, et al. Endothelial cells are progenitors of cardiac pericytes and vascular smooth muscle cells. Nat Commun 2016; 7: 12422.
94. Tamosiuniene R, Tian W, Dhillon G, et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res 2011; 109: 867–879.
95. Lahm T, Tuder RM, Petrache I. Progress in solving the sex hormone paradox in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2014; 307: L7–L26.
96. Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the COMPERA registry. Circulation 2014; 129: 57–65.
97. Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med 2012; 186: 790–796.
98. 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.
99. Jing ZC, Xu XQ, Han ZY, et al. Registry and survival study in Chinese patients with idiopathic and familial pulmonary arterial hypertension. Chest 2007; 132: 373–379.
100. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006; 173: 1023–1030.
101. Peacock AJ, Murphy NF, McMurray JJ, et al. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007; 30: 104–109.
102. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010; 137: 376–387.
103. Hampole CV, Mehrotra AK, Thenappan T, et al. Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension. Am J Cardiol 2009; 104: 868–872.
104. Krasuski RA, Hart SA, Smith B, et al. Association of anemia and long-term survival in patients with pulmonary hypertension. Int J Cardiol 2011; 150: 291–295.
105. Ball MK, Waypa GB, Mungai PT, et al. Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. Am J Respir Crit Care Med 2014; 189: 314–324.
106. Reeves JT, Grover RF. Insights by Peruvian scientists into the pathogenesis of human chronic hypoxic pulmonary hypertension. J Appl Physiol 2004; 98: 384–389.