Pathology and Pathobiology of Pulmonary Hypertension

Christophe Guignabert; Peter Dorfmüller

doi:10.1055/s-0037-1606214

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2017; 38(05): 571-584
DOI: 10.1055/s-0037-1606214

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Pathology and Pathobiology of Pulmonary Hypertension

Authors

Christophe Guignabert

¹INSERM UMR_S 999, “Pulmonary Hypertension: Physiopathology and Novel Therapies,” Le Plessis-Robinson, Paris, France

²University of Paris-Sud/Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, Paris, France
Peter Dorfmüller

¹INSERM UMR_S 999, “Pulmonary Hypertension: Physiopathology and Novel Therapies,” Le Plessis-Robinson, Paris, France

²University of Paris-Sud/Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, Paris, France

³Pathology Department, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France

Abstract

Pulmonary hypertension (PH) is a hemodynamic state defined by a mean pulmonary artery pressure ≥ 25 mm Hg during resting right heart catheterization. PH can result from precapillary (arterial) or postcapillary (venous) pathophysiological mechanisms. Interestingly, recent PH pathology has shown that pulmonary arterial or pulmonary venous remodelling are rarely independent phenomena, but frequently occur in combined fashion in lungs from patients suffering from different forms of PH, including pulmonary arterial hypertension (PAH). In PAH, it is now becoming clear that aberrant signals present in vessel wall microenvironment, which is largely orchestrated by dysfunctional pulmonary endothelial cells, are key contributors of the pulmonary vascular remodeling process, fostering proliferation, and survival and migration of resident pulmonary vascular cells such as smooth muscle cells, myofibroblasts, and pericytes. In addition, both genetic and environmental factors are also critical in the development of pulmonary vascular inflammation and chronic impairment of the pulmonary endothelium. This article outlines the current understanding of this disease from the point of view of pathology and pathobiology.

Keywords

pulmonary arterial hypertension - pulmonary vascular remodeling - endothelial dysfunction - inflammation - BMPR2

Full Text

References

References
1 Galiè N, Humbert M, Vachiery JL. , 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 Respir J 2015; 46 (04) 903-975
2 Simonneau G, Gatzoulis MA, Adatia I. , et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (25, Suppl): D34-D41
3 Guignabert C, Dorfmuller P. Pathology and pathobiology of pulmonary hypertension. Semin Respir Crit Care Med 2013; 34 (05) 551-559
4 Humbert M, Sitbon O, Chaouat A. , et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010; 122 (02) 156-163
5 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 (09) 1023-1030
6 Humbert M, Sitbon O, Yaïci A. , et al; French Pulmonary Arterial Hypertension Network. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010; 36 (03) 549-555
7 Guignabert C, Tu L, Girerd B. , et al. New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: importance of endothelial communication. Chest 2015; 147 (02) 529-537
8 Schäfer M, Kheyfets VO, Schroeder JD. , et al. Main pulmonary arterial wall shear stress correlates with invasive hemodynamics and stiffness in pulmonary hypertension. Pulm Circ 2016; 6 (01) 37-45
9 Wang Z, Chesler NC. Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension. Pulm Circ 2011; 1 (02) 212-223
10 Montani D, Lau EM, Dorfmüller P. , et al. Pulmonary veno-occlusive disease. Eur Respir J 2016; 47 (05) 1518-1534
11 Dorfmüller P, Günther S, Ghigna MR. , et al. Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature. Eur Respir J 2014; 44 (05) 1275-1288
12 Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J 2008; 32 (05) 1371-1385
13 Ghigna MR, Guignabert C, Montani D. , et al. BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension. Eur Respir J 2016; 48 (06) 1668-1681
14 Hoeper MM, Lam CS, Vachiery JL. , et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a plea for proper phenotyping and further research†. Eur Heart J 2016;
15 Colombat M, Mal H, Groussard O. , et al. Pulmonary vascular lesions in end-stage idiopathic pulmonary fibrosis: histopathologic study on lung explant specimens and correlations with pulmonary hemodynamics. Hum Pathol 2007; 38 (01) 60-65
16 Nunes H, Humbert M, Capron F. , et al. Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis. Thorax 2006; 61 (01) 68-74
17 Fartoukh M, Humbert M, Capron F. , et al. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med 2000; 161 (01) 216-223
18 Huertas A, Girerd B, Dorfmuller P, O'Callaghan D, Humbert M, Montani D. Pulmonary veno-occlusive disease: advances in clinical management and treatments. Expert Rev Respir Med 2011; 5 (02) 217-229 , quiz 230–231
19 Aramendia P, De Letona JM, Aviado DM. Exchange of blood between pulmonary and systemic circulations via bronchopulmonary anastomoses. Circ Res 1962; 11: 870-879
20 Hasegawa I, Kobayashi K, Kohda E, Hiramatsu K. Bronchopulmonary arterial anastomosis at the precapillary level in human lung. Visualization using CT angiography compared with microangiography of autopsied lung. Acta Radiol 1999; 40 (06) 578-584
21 Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 1958; 18 (4, Part 1): 533-547
22 Heath D, Williams D. High-Altitude Medicine and Pathology. London: Butterworths; 1989
23 Voelkel NF, Tuder RM. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J 1995; 8 (12) 2129-2138
24 Cool CD, Kennedy D, Voelkel NF, Tuder RM. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 1997; 28 (04) 434-442
25 Wagenvoort C, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42: 1163-1184
26 Krowka MJ, Edwards WD. A spectrum of pulmonary vascular pathology in portopulmonary hypertension. Liver Transpl 2000; 6 (02) 241-242
27 Widgren S. [Prolonged survey of cases of pulmonary hypertension in relation to consumption of aminorex. Histological, quantitative and morphometric study of 9 cases]. Schweiz Med Wochenschr 1986; 116 (27-28): 918-924
28 Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993; 103 (03) 685-692
29 Harrison CV. IV. The pathology of the pulmonary vessels in pulmonary hypertension. Br J Radiol 1958; 31 (364) 217-226
30 Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2011; 364 (04) 351-360
31 Tuder RM, Abman SH, Braun T. , et al. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S3-S9
32 Galambos C, Sims-Lucas S, Abman SH, Cool CD. Intrapulmonary bronchopulmonary anastomoses and plexiform lesions in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2016; 193 (05) 574-576
33 Yaginuma G, Mohri H, Takahashi T. Distribution of arterial lesions and collateral pathways in the pulmonary hypertension of congenital heart disease: a computer aided reconstruction study. Thorax 1990; 45 (08) 586-590
34 Stacher E, Graham BB, Hunt JM. , et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186 (03) 261-272
35 Dorfmüller P, Zarka V, Durand-Gasselin I. , et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165 (04) 534-539
36 Balabanian K, Foussat A, Dorfmüller P. , et al. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165 (10) 1419-1425
37 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 (10) 1041-1047
38 Dorfmüller P, Humbert M, Capron F, Müller KM. Pathology and aspects of pathogenesis in pulmonary arterial hypertension. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20 (01) 9-19
39 Perros F, Dorfmüller P, Souza R. , et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 2007; 29 (05) 937-943
40 Galiè N, Kim NH. Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc 2006; 3 (07) 571-576
41 Pietra G. Pathology of Primary pulmonary hypertension. New York: Marcel Dekker; 1997
42 Pietra GG, Capron F, Stewart S. , et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004; 43 (12, Suppl S): 25S-32S
43 Golde DW, Drew WL, Klein HZ, Finley TN, Cline MJ. Occult pulmonary haemorrhage in leukaemia. BMJ 1975; 2 (5964): 166-168
44 Capron F. [Bronchoalveolar lavage and alveolar hemorrhage]. Ann Pathol 1999; 19 (05) 395-400
45 Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest 2006; 130 (02) 545-552
46 Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 2011; 8 (08) 443-455
47 White RJ, Meoli DF, Swarthout RF. , et al. Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007; 293 (03) L583-L590
48 Chaouat A, Weitzenblum E, Higenbottam T. The role of thrombosis in severe pulmonary hypertension. Eur Respir J 1996; 9 (02) 356-363
49 Atherton A, Born GV. Quantitative investigations of the adhesiveness of circulating polymorphonuclear leucocytes to blood vessel walls. J Physiol 1972; 222 (02) 447-474
50 Moore KL, Esmon CT, Esmon NL. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood 1989; 73 (01) 159-165
51 van Hinsbergh VW. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol 2012; 34 (01) 93-106
52 Chaudhary KR, Taha M, Cadete VJ, Godoy RS, Stewart DJ. Proliferative versus degenerative paradigms in pulmonary arterial hypertension: have we put the cart before the horse?. Circ Res 2017; 120 (08) 1237-1239
53 Taraseviciene-Stewart L, Kasahara Y, Alger L. , 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 (02) 427-438
54 Jurasz P, Courtman D, Babaie S, Stewart DJ. Role of apoptosis in pulmonary hypertension: from experimental models to clinical trials. Pharmacol Ther 2010; 126 (01) 1-8
55 Granton J, Langleben D, Kutryk MB. , et al. Endothelial NO-Synthase gene-enhanced progenitor cell therapy for pulmonary arterial hypertension: the PHACeT trial. Circ Res 2015; 117 (07) 645-654
56 Papaioannou AI, Zakynthinos E, Kostikas K. , et al. Serum VEGF levels are related to the presence of pulmonary arterial hypertension in systemic sclerosis. BMC Pulm Med 2009; 9: 18
57 Tuder RM, Chacon M, Alger L. , et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol 2001; 195 (03) 367-374
58 Hirose S, Hosoda Y, Furuya S, Otsuki T, Ikeda E. Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension. Pathol Int 2000; 50 (06) 472-479
59 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 (04) 474-484
60 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 (03) 512-523
61 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 (02) 311-322
62 Tu L, De Man FS, Girerd B. , et al. A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents. Am J Respir Crit Care Med 2012; 186 (07) 666-676
63 Li X, Zhang X, Leathers R. , et al. Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat Med 2009; 15 (11) 1289-1297
64 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 (15) 1586-1597
65 Yuan K, Orcholski ME, Panaroni C. , et al. Activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis. Am J Pathol 2015; 185 (01) 69-84
66 Masri FA, Xu W, Comhair SA. , et al. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007; 293 (03) L548-L554
67 Patel M, Predescu D, Tandon R. , et al. A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension. J Biol Chem 2013; 288 (52) 36855 . [Corrected in J Biol Chem 2013;288(52):36855]
68 Kudryashova TV, Goncharov DA, Pena A. , et al. HIPPO-integrin-linked kinase cross-talk controls self-sustaining proliferation and survival in pulmonary hypertension. Am J Respir Crit Care Med 2016; 194 (07) 866-877
69 Le Hiress M, Tu L, Ricard N. , et al. Proinflammatory signature of the dysfunctional endothelium in pulmonary hypertension. Role of the macrophage migration inhibitory factor/CD74 complex. Am J Respir Crit Care Med 2015; 192 (08) 983-997
70 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 (18) 1783-1794
71 Ranchoux B, Antigny F, Rucker-Martin C. , et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 2015; 131 (11) 1006-1018
72 Stenmark KR, Frid M, Perros F. Endothelial-to-mesenchymal transition: an evolving paradigm and a promising therapeutic target in PAH. Circulation 2016; 133 (18) 1734-1737
73 de Jesus Perez VA, Yuan K, Orcholski ME. , et al. Loss of adenomatous poliposis coli-α3 integrin interaction promotes endothelial apoptosis in mice and humans. Circ Res 2012; 111 (12) 1551-1564
74 Fijalkowska I, Xu W, Comhair SA. , et al. Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol 2010; 176 (03) 1130-1138
75 Xu W, Koeck T, Lara AR. , et al. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci U S A 2007; 104 (04) 1342-1347
76 Eddahibi S, Guignabert C, Barlier-Mur AM. , et al. Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Circulation 2006; 113 (15) 1857-1864
77 Guignabert C, Raffestin B, Benferhat R. , et al. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 2005; 111 (21) 2812-2819
78 Fernandez RA, Wan J, Song S. , et al. Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype. Am J Physiol Cell Physiol 2015; 308 (08) C581-C593
79 Guignabert C, Tu L, Izikki M. , et al. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. FASEB J 2009; 23 (12) 4135-4147
80 Eddahibi S, Humbert M, Fadel E. , et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001; 108 (08) 1141-1150
81 McMurtry MS, Archer SL, Altieri DC. , et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005; 115 (06) 1479-1491
82 Hameed AG, Arnold ND, Chamberlain J. , et al. Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension. J Exp Med 2012; 209 (11) 1919-1935
83 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 (11) 1289-1300
84 Noureddine H, Gary-Bobo G, Alifano M. , et al. Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease. Circ Res 2011; 109 (05) 543-553
85 Mouraret N, Marcos E, Abid S. , et al. Activation of lung p53 by Nutlin-3a prevents and reverses experimental pulmonary hypertension. Circulation 2013; 127 (16) 1664-1676
86 McMurtry MS, Bonnet S, Wu X. , et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 2004; 95 (08) 830-840
87 Zhao L, Chen CN, Hajji N. , et al. Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation 2012; 126 (04) 455-467
88 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 (22) 2630-2641
89 Yuan XJ. Voltage-gated K+ currents regulate resting membrane potential and [Ca2+]i in pulmonary arterial myocytes. Circ Res 1995; 77 (02) 370-378
90 Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 2008; 294 (02) H570-H578
91 Yu Y, Platoshyn O, Zhang J. , et al. c-Jun decreases voltage-gated K(+) channel activity in pulmonary artery smooth muscle cells. Circulation 2001; 104 (13) 1557-1563
92 Anwar A, Li M, Frid MG. , et al. Osteopontin is an endogenous modulator of the constitutively activated phenotype of pulmonary adventitial fibroblasts in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2012; 303 (01) L1-L11
93 Das M, Burns N, Wilson SJ, Zawada WM, Stenmark KR. Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKCzeta in the pulmonary artery adventitia. Cardiovasc Res 2008; 78 (03) 440-448
94 Panzhinskiy E, Zawada WM, Stenmark KR, Das M. Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGFβ receptor-JNK1 signalling. Cardiovasc Res 2012; 95 (03) 356-365
95 Wang D, Zhang H, Li M. , et al. MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ Res 2014; 114 (01) 67-78
96 Li M, Riddle SR, Frid MG. , et al. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol 2011; 187 (05) 2711-2722
97 Izikki M, Hoang E, Draskovic I. , et al. Telomere maintenance is a critical determinant in the physiopathology of pulmonary hypertension. J Am Coll Cardiol 2015; 66 (17) 1942-1943
98 Guignabert C, Tu L, Le Hiress M. , et al. Pathogenesis of pulmonary arterial hypertension: lessons from cancer. Eur Respir Rev 2013; 22 (130) 543-551
99 O'Callaghan DS, Savale L, Montani D. , et al. Treatment of pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol 2011; 8 (09) 526-538
100 Humbert M, Morrell NW, Archer SL. , et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43 (12, Suppl S): 13S-24S
101 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351 (14) 1425-1436
102 Arciniegas E, Frid MG, Douglas IS, Stenmark KR. Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2007; 293 (01) L1-L8
103 Lapel M, Weston P, Strassheim D. , et al. Glycolysis and oxidative phosphorylation are essential for purinergic receptor-mediated angiogenic responses in vasa vasorum endothelial cells. Am J Physiol Cell Physiol 2017; 312 (01) C56-C70
104 Huertas A, Perros F, Tu L. , et al. Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: a complex interplay. Circulation 2014; 129 (12) 1332-1340
105 Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014; 115 (01) 165-175
106 de Man FS, Tu L, Handoko ML. , et al. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186 (08) 780-789
107 Huertas A, Phan C, Bordenave J. , et al. Regulatory T cell dysfunction in idiopathic, heritable and connective tissue-associated pulmonary arterial hypertension. Chest 2016; 149 (06) 1482-1493
108 Huertas A, Tu L, Gambaryan N. , et al. Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J 2012; 40 (04) 895-904
109 Huertas A, Tu L, Thuillet R. , et al. Leptin signalling system as a target for pulmonary arterial hypertension therapy. Eur Respir J 2015; 45 (04) 1066-1080
110 Freund-Michel V, Cardoso Dos Santos M, Guignabert C. , et al. Role of nerve growth factor in development and persistence of experimental pulmonary hypertension. Am J Respir Crit Care Med 2015; 192 (03) 342-355
111 Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 1997; 277 (5323): 225-228
112 Rabinovitch M. Pathobiology of pulmonary hypertension. Extracellular matrix. Clin Chest Med 2001; 22 (03) 433-449 , viii
113 Shang M, Koshikawa N, Schenk S, Quaranta V. The LG3 module of laminin-5 harbors a binding site for integrin alpha3beta1 that promotes cell adhesion, spreading, and migration. J Biol Chem 2001; 276 (35) 33045-33053
114 Ma W, Han W, Greer PA. , et al. Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease. J Clin Invest 2011; 121 (11) 4548-4566
115 Wei L, Warburton RR, Preston IR. , et al. Serotonylated fibronectin is elevated in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2012; 302 (12) L1273-L1279
116 Jones PL, Rabinovitch M. Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ Res 1996; 79 (06) 1131-1142
117 Jones PL, Crack J, Rabinovitch M. Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J Cell Biol 1997; 139 (01) 279-293
118 Cowan KN, Jones PL, Rabinovitch M. Regression of hypertrophied rat pulmonary arteries in organ culture is associated with suppression of proteolytic activity, inhibition of tenascin-C, and smooth muscle cell apoptosis. Circ Res 1999; 84 (10) 1223-1233
119 Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 2000; 105 (01) 21-34
120 Huber K, Beckmann R, Frank H, Kneussl M, Mlczoch J, Binder BR. Fibrinogen, t-PA, and PAI-1 plasma levels in patients with pulmonary hypertension. Am J Respir Crit Care Med 1994; 150 (04) 929-933
121 Christ G, Graf S, Huber-Beckmann R. , et al. Impairment of the plasmin activation system in primary pulmonary hypertension: evidence for gender differences. Thromb Haemost 2001; 86 (02) 557-562
122 Katta S, Vadapalli S, Sastry BK, Nallari P. t-plasminogen activator inhibitor-1 polymorphism in idiopathic pulmonary arterial hypertension. Indian J Hum Genet 2008; 14 (02) 37-40
123 Kouri FM, Queisser MA, Königshoff M. , et al. Plasminogen activator inhibitor type 1 inhibits smooth muscle cell proliferation in pulmonary arterial hypertension. Int J Biochem Cell Biol 2008; 40 (09) 1872-1882
124 Dupont S, Morsut L, Aragona M. , et al. Role of YAP/TAZ in mechanotransduction. Nature 2011; 474 (7350): 179-183
125 Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev 2014; 94 (04) 1287-1312
126 Bertero T, Oldham WM, Cottrill KA. , et al. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest 2016; 126 (09) 3313-3335
127 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 Reports 2015; 13 (05) 1016-1032
128 Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 2000; 6 (06) 698-702
129 Kerr JS, Riley DJ, Frank MM, Trelstad RL, Frankel HM. Reduction of chronic hypoxic pulmonary hypertension in the rat by beta-aminopropionitrile. J Appl Physiol 1984; 57 (06) 1760-1766
130 Kerr JS, Ruppert CL, Tozzi CA. , et al. Reduction of chronic hypoxic pulmonary hypertension in the rat by an inhibitor of collagen production. Am Rev Respir Dis 1987; 135 (02) 300-306
131 Nave AH, Mižíková I, Niess G. , et al. Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2014; 34 (07) 1446-1458
132 Ilkiw R, Todorovich-Hunter L, Maruyama K, Shin J, Rabinovitch M. SC-39026, a serine elastase inhibitor, prevents muscularization of peripheral arteries, suggesting a mechanism of monocrotaline-induced pulmonary hypertension in rats. Circ Res 1989; 64 (04) 814-825
133 Maruyama K, Ye CL, Woo M. , et al. Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity. Am J Physiol 1991; 261 (6, Pt 2): H1716-H1726
134 Zaidi SH, You XM, Ciura S, Husain M, Rabinovitch M. Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 2002; 105 (04) 516-521
135 Izikki M, Hanoun N, Marcos E. , et al. Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 2007; 293 (04) L1045-L1052
136 Morecroft I, White K, Caruso P. , et al. Gene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial Tph1 attenuates hypoxia-induced pulmonary hypertension. Mol Ther 2012; 20 (08) 1516-1528
137 Aiello RJ, Bourassa PA, Zhang Q. , et al. Tryptophan hydroxylase 1 inhibition impacts pulmonary vascular remodeling in two rat models of pulmonary hypertension. J Pharmacol Exp Ther 2017; 360 (02) 267-279
138 Alastalo TP, Li M, Perez VdeJ. , et al. Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J Clin Invest 2011; 121 (09) 3735-3746
139 Kim J. Apelin-APJ signaling: a potential therapeutic target for pulmonary arterial hypertension. Mol Cells 2014; 37 (03) 196-201
140 Abe K, Shimokawa H, Morikawa K. , et al. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 2004; 94 (03) 385-393
141 Fagan KA, Oka M, Bauer NR. , et al. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol 2004; 287 (04) L656-L664
142 Guilluy C, Eddahibi S, Agard C. , et al. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med 2009; 179 (12) 1151-1158
143 Nagaoka T, Fagan KA, Gebb SA. , et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005; 171 (05) 494-499
144 Nagaoka T, Morio Y, Casanova N. , et al. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 2004; 287 (04) L665-L672
145 Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 1996; 392 (02) 189-193
146 Oka M, Homma N, Taraseviciene-Stewart L. , et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 2007; 100 (06) 923-929
147 Mouchaers KT, Schalij I, de Boer MA. , et al. Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil. Eur Respir J 2010; 36 (04) 800-807
148 Long L, Ormiston ML, Yang X. , et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 2015; 21 (07) 777-785
149 Wang G, Fan R, Ji R. , et al. Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: a case report. BMC Pulm Med 2016; 16: 17
150 Guignabert C, Bailly S, Humbert M. Restoring BMPRII functions in pulmonary arterial hypertension: opportunities, challenges and limitations. Expert Opin Ther Targets 2017; 21 (02) 181-190
151 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
152 Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep 2015; 42 (04) 841-851
153 Soni S, Padwad YS. HIF-1 in cancer therapy: two decade long story of a transcription factor. Acta Oncol 2017; 56 (04) 503-515
154 Corcoran SE, O'Neill LA. HIF1α and metabolic reprogramming in inflammation. J Clin Invest 2016; 126 (10) 3699-3707
155 Dai Z, Li M, Wharton J, Zhu MM, Zhao YY. 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-2α. Circulation 2016; 133 (24) 2447-2458
156 Barnes EA, Chen CH, Sedan O, Cornfield DN. Loss of smooth muscle cell hypoxia inducible factor-1α underlies increased vascular contractility in pulmonary hypertension. FASEB J 2017; 31 (02) 650-662
157 Segura-Ibarra V, Amione-Guerra J, Cruz-Solbes AS. , et al. Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension. Int J Pharm 2017; 524 (1-2): 257-267
158 Li L, Wang X, Wang L. , et al. Mammalian target of rapamycin overexpression antagonizes chronic hypoxia-triggered pulmonary arterial hypertension via the autophagic pathway. Int J Mol Med 2015; 36 (01) 316-322
159 Houssaini A, Abid S, Mouraret N. , et al. Rapamycin reverses pulmonary artery smooth muscle cell proliferation in pulmonary hypertension. Am J Respir Cell Mol Biol 2013; 48 (05) 568-577
160 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 (14) 1371-1385
161 Ma L, Roman-Campos D, Austin ED. , et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013; 369 (04) 351-361
162 Zhang Y, Xie X, Zhu Y. , et al. Inhibition of Notch3 prevents monocrotaline-induced pulmonary arterial hypertension. Exp Lung Res 2015; 41 (08) 435-443
163 Sawada H, Saito T, Nickel NP. , et al. Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J Exp Med 2014; 211 (02) 263-280
164 Qian J, Tian W, Jiang X. , et al. Leukotriene B4 activates pulmonary artery adventitial fibroblasts in pulmonary hypertension. Hypertension 2015; 66 (06) 1227-1239
165 Voelkel NF, Tamosiuniene R, Nicolls MR. Challenges and opportunities in treating inflammation associated with pulmonary hypertension. Expert Rev Cardiovasc Ther 2016; 14 (08) 939-951
166 Kawut SM, Bagiella E, Lederer DJ. , et al; ASA-STAT Study Group. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation 2011; 123 (25) 2985-2993
167 Shinomiya S, Naraba H, Ueno A. , et al. Regulation of TNFalpha and interleukin-10 production by prostaglandins I(2) and E(2): studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists. Biochem Pharmacol 2001; 61 (09) 1153-1160
168 Lindemann S, Gierer C, Darius H. Prostacyclin inhibits adhesion of polymorphonuclear leukocytes to human vascular endothelial cells due to adhesion molecule independent regulatory mechanisms. Basic Res Cardiol 2003; 98 (01) 8-15
169 Wang JW, Vu C, Poloso NJ. A prostacyclin analog, cicaprost, exhibits potent anti-inflammatory activity in human primary immune cells and a uveitis model. J Ocul Pharmacol Ther 2017; 33 (03) 186-192
170 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 (05) 1628-1631
171 Soon E, Holmes AM, Treacy CM. , et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 2010; 122 (09) 920-927
172 Dib H, Tamby MC, Bussone G. , et al. Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur Respir J 2012; 39 (06) 1405-1414
173 Terrier B, Tamby MC, Camoin L. , et al. Identification of target antigens of antifibroblast antibodies in pulmonary arterial hypertension. Am J Respir Crit Care Med 2008; 177 (10) 1128-1134
174 Tamby MC, Chanseaud Y, Humbert M. , et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 2005; 60 (09) 765-772
175 Guerreso K, Conner EA. Possible role of anti-SSA/Ro antibodies in the pathogenesis of pulmonary hypertension. Respir Med Case Rep 2016; 17: 47-49
176 Perros F, Dorfmüller P, Souza R. , et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J 2007; 29 (03) 462-468
177 Perros F, Dorfmüller P, Montani D. , et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 185 (03) 311-321
178 Tamby MC, Humbert M, Guilpain P. , et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J 2006; 28 (04) 799-807
179 Rich S, Kieras K, Hart K, Groves BM, Stobo JD, Brundage BH. Antinuclear antibodies in primary pulmonary hypertension. J Am Coll Cardiol 1986; 8 (06) 1307-1311
180 Tcherakian C, Rivaud E, Zucman D, Metivier AC, Couderc LJ. Curing HIV-associated pulmonary arterial hypertension. Eur Respir J 2012; 39 (04) 1045-1046
181 Degano B, Guillaume M, Savale L. , et al. HIV-associated pulmonary arterial hypertension: survival and prognostic factors in the modern therapeutic era. AIDS 2010; 24 (01) 67-75
182 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 (02) 521-531
183 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 (02) 219-228
184 Li M, Vattulainen S, Aho J. , 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 2014; 50 (06) 1118-1128
185 Chen NY, , D Collum S, Luo F. , et al. Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2016; 311 (02) L238-L254
186 D K, v Y, A D, Br KV, S B. Tubercular aortitis presenting as severe mesenteric ischemia and hypertension. J Assoc Physicians India 2016; 64 (01) 117
187 Diebold I, Hennigs JK, Miyagawa K. , et al. BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. Cell Metab 2015; 21 (04) 596-608
188 Soon E, Crosby A, Southwood M. , 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 2015; 192 (07) 859-872
189 Hagen M, Fagan K, Steudel W. , et al. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol 2007; 292 (06) L1473-L1479
190 Hong KH, Lee YJ, Lee E. , et al. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation 2008; 118 (07) 722-730
191 Song Y, Coleman L, Shi J. , et al. Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. Am J Physiol Heart Circ Physiol 2008; 295 (02) H677-H690