Targeting Vascular Remodeling to Treat Pulmonary Arterial Hypertension

Trends in Molecular Medicine

Volumn 23, Issue 1, 2017, Pages 31-45

  Thompson, A A Roger ^a   Lawrie, Allan ^a  

^a UNIVERSITY OF SHEFFIELD   (United Kingdom)

Author keywords

BMPR2; hypoxia; miRNA; pulmonary hypertension; vascular remodeling

Indexed keywords

BONE MORPHOGENETIC PROTEIN RECEPTOR 2; CYTOKINE; INTERLEUKIN 6; INTERLEUKIN 8; MICRORNA; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND; BMPR2 PROTEIN, HUMAN;

CELL METABOLISM; DISEASE PREDISPOSITION; DNA DAMAGE; EPIGENETIC REPRESSION; GENE MUTATION; GENETICS; HEREDITY; HUMAN; HYPOXIA; INFLAMMATION; PATHOGENESIS; PROTEIN DEFECT; PULMONARY HYPERTENSION; REVIEW; SEX RATIO; SIGNAL TRANSDUCTION; VASCULAR REMODELING; WHOLE EXOME SEQUENCING; ANIMAL; DRUG DEVELOPMENT; DRUG EFFECTS; HYPERTENSION, PULMONARY; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PATHOPHYSIOLOGY; PULMONARY ARTERY;

ANIMALS; BONE MORPHOGENETIC PROTEIN RECEPTORS, TYPE II; DRUG DISCOVERY; HUMANS; HYPERTENSION, PULMONARY; HYPOXIA; MICRORNAS; MOLECULAR TARGETED THERAPY; PULMONARY ARTERY; SIGNAL TRANSDUCTION; VASCULAR REMODELING;

EID: 85007407742     PISSN: 14714914     EISSN: 1471499X     Source Type: Journal    
DOI: 10.1016/j.molmed.2016.11.005     Document Type: Review

References (114)

1. 1 Simonneau, G., et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 62 (2013), D34–D41.
2. 2 Stacher, E., et al. Modern age pathology of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 186 (2012), 261–272.
3. 3 Rabinovitch, M., Molecular pathogenesis of pulmonary arterial hypertension. J. Clin. Invest. 122 (2012), 4306–4313.
4. 4 Hurdman, J., et al. ASPIRE registry: assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre. Eur. Respir. J. 39 (2012), 945–955.
5. 5 Farber, H.W., et al. Five-Year outcomes of patients enrolled in the REVEAL Registry. Chest 148 (2015), 1043–1054.
6. 6 Ling, Y., 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. 186 (2012), 790–796.
7. 7 International, P.P.H.C., et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat. Genet. 26 (2000), 81–84.
8. 8 Deng, Z., et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am. J. Hum. Genet. 67 (2000), 737–744.
9. 9 Rosenzweig, B.L., et al. Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc. Natl. Acad. Sci. U.S.A. 92 (1995), 7632–7636.
10. 10 Nohno, T., et al. Identification of a human type-Ii receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type-I receptors. J. Biol. Chem. 270 (1995), 22522–22526.
11. 11 David, L., et al. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109 (2007), 1953–1961.
12. 12 Morrell, N.W., et al. Targeting BMP signalling in cardiovascular disease and anaemia. Nat. Rev. Cardiol. 13 (2016), 106–120.
13. 13 Liu, F., et al. A human Mad protein acting as a BMP-regulated transcriptional activator. Nature 381 (1996), 620–623.
14. 14 Machado, R.D., et al. Pulmonary arterial hypertension: a current perspective on established and emerging molecular genetic defects. Hum. Mutat. 36 (2015), 1113–1127.
15. 15 Atkinson, C., et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105 (2002), 1672–1678.
16. 16 Newman, J.H., et al. 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 (2001), 319–324.
17. 17 Hong, K.H., et al. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation 118 (2008), 722–730.
18. 18 West, J., et al. Suppression of type II bone morphogenic protein receptor in vascular smooth muscle induces pulmonary arterial hypertension in transgenic mice. Chest, 128, 2005, 553S.
19. 19 Long, L., et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat. Med. 21 (2015), 777–785.
20. 20 Ranchoux, B., et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 131 (2015), 1006–1018.
21. 21 Hopper, R.K., et al. In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to-mesenchymal transition via HMGA1 and its target Slug. Circulation 133 (2016), 1783–1794.
22. 22 Diebold, I., et al. BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. Cell Metab. 21 (2015), 596–608.
23. 23 Austin, E.D., et al. BMPR2 expression is suppressed by signaling through the estrogen receptor. Biol. Sex Differ., 3, 2012, 6.
24. 24 Mair, K.M., et al. Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells. Am. J. Respir. Crit. Care Med. 191 (2015), 693–703.
25. 25 Mair, K.M., et al. Sex-dependent influence of endogenous estrogen in pulmonary hypertension. Am. J. Respir. Crit. Care Med. 190 (2014), 456–467.
26. 26 Ventetuolo, C.E., et al. Higher estradiol and lower dehydroepiandrosterone-sulfate levels are associated with pulmonary arterial hypertension in men. Am. J. Respir. Crit. Care Med. 193 (2016), 1168–1175.
27. 27 Swift, A.J., et al. Right ventricular sex differences in patients with idiopathic pulmonary arterial hypertension characterised by magnetic resonance imaging: pair-matched case controlled study. PLoS One, 10, 2015, e0127415.
28. 28 Jacobs, W., et al. The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest 145 (2014), 1230–1236.
29. 29 Alzoubi, A., et al. Dehydroepiandrosterone restores right ventricular structure and function in rats with severe pulmonary arterial hypertension. Am. J. Physiol. Heart Circ. Physiol. 304 (2013), H1708–H1718.
30. 30 Lahm, T., et al. Progress in solving the sex hormone paradox in pulmonary hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 307 (2014), L7–L26.
31. 31 Spiekerkoetter, E., et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J. Clin. Invest. 123 (2013), 3600–3613.
32. 32 Spiekerkoetter, E., et al. Low-dose FK506 (tacrolimus) in end-stage pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 192 (2015), 254–257.
33. 33 Dunmore, B.J., et al. The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations. Hum. Mol. Genet. 22 (2013), 3667–3679.
34. 34 Burton, V.J., et al. Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function. Blood 117 (2011), 333–341.
35. 35 Zhu, H., et al. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400 (1999), 687–693.
36. 36 Rothman, A.M., et al. MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. J. Clin. Invest. 126 (2016), 2495–2508.
37. 37 Barnes, J.W., et al. BMPR2 mutation-independent mechanisms of disrupted BMP signaling in IPAH. Am. J. Respir. Cell Mol. Biol., 2016, 10.1165/rcmb.2015-0402OC.
38. 38 Cao, Y., et al. Selective small molecule compounds increase BMP-2 responsiveness by inhibiting Smurf1-mediated Smad1/5 degradation. Sci. Rep., 4, 2014, 4965.
39. 39 Savai, R., et al. Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension. Nat. Med. 20 (2014), 1289–1300.
40. 40 Sowa, G., Caveolae, caveolins, cavins, and endothelial cell function: new insights. Front. Physiol., 2, 2012, 120.
41. 41 Prewitt, A.R., et al. Heterozygous null bone morphogenetic protein receptor type 2 mutations promote SRC kinase-dependent caveolar trafficking defects and endothelial dysfunction in pulmonary arterial hypertension. J. Biol. Chem. 290 (2015), 960–971.
42. 42 Ma, L., et al. A novel channelopathy in pulmonary arterial hypertension. N. Engl. J. Med. 369 (2013), 351–361.
43. 43 Antigny, F., et al. Potassium channel subfamily K member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension. Circulation 133 (2016), 1371–1385.
44. 44 de Jesus Perez, V.A., et al. Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 189 (2014), 1260–1272.
45. 45 Germain, M., et al. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat. Genet. 45 (2013), 518–521.
46. 46 Rhodes, C.J., et al. Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 187 (2013), 294–302.
47. 47 Schlosser, K., et al. Discordant regulation of microRNA between multiple experimental models and human pulmonary hypertension. Chest 148 (2015), 481–490.
48. 48 Meloche, J., et al. miR-223 reverses experimental pulmonary arterial hypertension. Am. J. Physiol. Cell Physiol. 309 (2015), C363–C372.
49. 49 Bertero, T., et al. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J. Clin. Invest. 124 (2014), 3514–3528.
50. 50 Alastalo, T.P., et al. Disruption of PPARgamma/beta-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J. Clin. Invest. 121 (2011), 3735–3746.
51. 51 Courboulin, A., et al. Role for miR-204 in human pulmonary arterial hypertension. J. Exp. Med. 208 (2011), 535–548.
52. 52 Kim, J., et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat. Med. 19 (2013), 74–82.
53. 53 Chun, H.J., et al. Translating microRNA biology in pulmonary hypertension: it will take more than “miR” words. Am. J. Respir. Crit. Care Med., 2016, 10.1164/rccm.201604–0886PP.
54. 54 Stenmark, K.R., et al. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am. J. Physiol. Lung Cell Mol. Physiol. 297 (2009), L1013–L1032.
55. 55 Bartsch, P., Gibbs, J.S., Effect of altitude on the heart and the lungs. Circulation 116 (2007), 2191–2202.
56. 56 Semenza, G.L., Hypoxia-inducible factors in physiology and medicine. Cell 148 (2012), 399–408.
57. 57 Maxwell, P.H., et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399 (1999), 271–275.
58. 58 Yu, A.Y., et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J. Clin. Invest. 103 (1999), 691–696.
59. 59 Brusselmans, K., et al. Heterozygous deficiency of hypoxia-inducible factor-2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J. Clin. Invest. 111 (2003), 1519–1527.
60. 60 Tuder, R.M., et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J. Pathol. 195 (2001), 367–374.
61. 61 Dai, Z., et al. Prolyl-4 hydroxylase 2 (PHD2) deficiency in endothelial cells and hematopoietic cells induces obliterative vascular remodeling and severe pulmonary arterial hypertension in mice and humans through hypoxia-inducible factor-2alpha. Circulation 133 (2016), 2447–2458.
62. 62 Kapitsinou, P.P., et al. The endothelial prolyl-4-hydroxylase domain 2/hypoxia-inducible factor 2 Axis regulates pulmonary artery pressure in mice. Mol. Cell. Biol. 36 (2016), 1584–1594.
63. 63 Gale, D.P., et al. Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation. Blood 112 (2008), 919–921.
64. 64 Gordeuk, V.R., et al. Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood 103 (2004), 3924–3932.
65. 65 Smith, T.G., et al. Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary physiology. PLoS Med., 3, 2006, e290.
66. 66 Cowburn, A.S., et al. HIF2alpha-arginase axis is essential for the development of pulmonary hypertension. Proc. Natl. Acad. Sci. U.S.A. 113 (2016), 8801–8806.
67. 67 Galie, N., et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur. Heart J. 37 (2016), 67–119.
68. 68 Zhao, L., et al. The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia. Nature 524 (2015), 356–360.
69. 69 Maxwell, P.H., Eckardt, K.U., HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat. Rev. Nephrol. 12 (2016), 157–168.
70. 70 Rabinovitch, M., et al. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ. Res. 115 (2014), 165–175.
71. 71 Soon, E., et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122 (2010), 920–927.
72. 72 Humbert, M., et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 151 (1995), 1628–1631.
73. 73 Soon, E., et al. Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 192 (2015), 859–872.
74. 74 Sawada, H., et al. Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J. Exp. Med. 211 (2014), 263–280.
75. 75 Eyries, M., et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat. Genet. 46 (2014), 65–69.
76. 76 Best, D.H., et al. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest 145 (2014), 231–236.
77. 77 Tian, W., et al. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci. Transl. Med., 5, 2013, 200ra117.
78. 78 Steiner, M.K., et al. Interleukin-6 overexpression induces pulmonary hypertension. Circ. Res. 104 (2009), 236–244.
79. 79 Lawrie, A., et al. Paigen diet-fed apolipoprotein E knockout mice develop severe pulmonary hypertension in an interleukin-1-dependent manner. Am. J. Pathol. 179 (2011), 1693–1705.
80. 80 Lawrie, A., et al. Evidence of a role for osteoprotegerin in the pathogenesis of pulmonary arterial hypertension. Am. J. Pathol. 172 (2008), 256–264.
81. 81 Hameed, A.G., et al. Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension. J. Exp. Med. 209 (2012), 1919–1935.
82. 82 Condliffe, R., et al. Serum osteoprotegerin is increased and predicts survival in idiopathic pulmonary arterial hypertension. Pulm Circ 2 (2012), 21–27.
83. 83 Dawson, S., Lawrie, A., From bones to blood pressure, developing novel biologic approaches targeting the osteoprotegein pathway for pulmonary vascular disease. Pharmacol. Ther., 2016 Published online July 1, 2016 http://dx.doi.org/10.1016/j.pharmthera.2016.06.017.
84. 84 Bonnet, S., et al. Translating research into improved patient care in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 2016, 10.1164/rccm.201607–1515PP.
85. 85 Pullamsetti, S.S., et al. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am. J. Respir. Crit. Care Med. 185 (2012), 409–419.
86. 86 Brock, M., et al. AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. Eur. Heart J. 35 (2014), 3203–3211.
87. 87 Yang, S., et al. miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am. J. Physiol. Lung Cell Mol. Physiol. 302 (2012), L521–L529.
88. 88 Wang, R., et al. Microrna-26b attenuates monocrotaline-induced pulmonary vascular remodeling via targeting connective tissue growth factor (CTGF) and cyclin D1 (CCND1). Oncotarget., 2016 Published online June 17, 2016 http://dx.doi.org/10.18632/oncotarget.10125.
89. 89 Bi, R., et al. MicroRNA-27b plays a role in pulmonary arterial hypertension by modulating peroxisome proliferator-activated receptor gamma dependent Hsp90-eNOS signaling and nitric oxide production. Biochem. Biophys. Res. Commun. 460 (2015), 469–475.
90. 90 Chen, X., 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 133 (2016), 82–97.
91. 91 Wang, P., et al. miRNA-34a promotes proliferation of human pulmonary artery smooth muscle cells by targeting PDGFRA. Cell Prolif. 49 (2016), 484–493.
92. 92 Wallace, E., et al. A sex-specific microRNA-96/5-hydroxytryptamine 1B axis influences development of pulmonary hypertension. Am. J. Respir. Crit. Care Med. 191 (2015), 1432–1442.
93. 93 Potus, F., et al. Downregulation of microRNA-126 contributes to the failing right ventricle in pulmonary arterial hypertension. Circulation 132 (2015), 932–943.
94. 94 Bertero, T., et al. Matrix remodeling promotes pulmonary hypertension through feedback mechanoactivation of the YAP/TAZ-miR-130/301 circuit. Cell Rep. 13 (2015), 1016–1032.
95. 95 Caruso, P., et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler. Thromb. Vasc. Biol. 30 (2010), 716–723.
96. 96 Sharma, S., et al. Apolipoprotein A-I mimetic peptide 4F rescues pulmonary hypertension by inducing microRNA-193-3p. Circulation 130 (2014), 776–785.
97. 97 Liu, Y., et al. MiRNA-199a-5p influences pulmonary artery hypertension via downregulating Smad3. Biochem. Biophys. Res. Commun. 473 (2016), 859–866.
98. 98 White, K., et al. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Mol. Med. 7 (2015), 695–713.
99. 99 Shi, L., et al. miR-223-IGF-IR signalling in hypoxia- and load-induced right-ventricular failure: a novel therapeutic approach. Cardiovasc. Res. 111 (2016), 184–193.
100. 100 Zamanian, R.T., et al. Insulin resistance in pulmonary arterial hypertension. Eur. Respir. J. 33 (2009), 318–324.
101. 101 Sutendra, G., Michelakis, E.D., The metabolic basis of pulmonary arterial hypertension. Cell Metab. 19 (2014), 558–573.
102. 102 Ryan, J.J., Archer, S.L., Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension. Circulation 131 (2015), 1691–1702.
103. 103 Sutendra, G., et al. Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFalpha contributes to the pathogenesis of pulmonary arterial hypertension. J. Mol. Med. (Berl.) 89 (2011), 771–783.
104. 104 Vander Heiden, M.G., et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324 (2009), 1029–1033.
105. 105 Paulin, R., et al. Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. Cell Metab. 20 (2014), 827–839.
106. 106 Bonnet, S., et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc. Natl. Acad. Sci. U.S.A. 104 (2007), 11418–11423.
107. 107 Bonnet, S., 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 113 (2006), 2630–2641.
108. 108 Paulin, R., et al. Signal transducers and activators of transcription-3/pim1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension. Circulation 123 (2011), 1205–1215.
109. 109 Brittain, E.L., et al. Fatty acid metabolic defects and right ventricular lipotoxicity in human pulmonary arterial hypertension. Circulation 133 (2016), 1936–1944.
110. 110 Lee, S.D., et al. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J. Clin. Invest. 101 (1998), 927–934.
111. 111 Aldred, M.A., et al. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 182 (2010), 1153–1160.
112. 112 Federici, C., et al. Increased mutagen sensitivity and DNA damage in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 192 (2015), 219–228.
113. 113 Li, M., et al. Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am. J. Respir. Cell Mol. Biol. 50 (2014), 1118–1128.
114. 114 Meloche, J., et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation 129 (2014), 786–797.