Abstract
The combination of pulmonary vasoconstriction, in situ thrombosis, and pulmonary arterial wall remodeling is largely responsible for the rise in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in patients with pulmonary arterial hypertension (PAH). Even though several drugs have been developed over the past decades, at this time there is no cure for PAH. The overriding goals of the current therapeutic options seek to compensate for the defects in the relative balance of competing vasoconstrictor and vasodilator influences. Because the past decade has seen great strides in our understanding of the pathogenesis of PAH, interest has been growing in the potential use of anti-proliferative approaches in PAH. Indeed anti-proliferative strategies could offer ways not only to reinstate the homeostatic balance between cell proliferation and apoptosis but also to reverse the progressive pulmonary vascular obstruction in PAH. However, further efforts still need to be made in order to establish the long-term safety and efficacy of those anti-proliferative approaches in PAH and their potential additive benefit with other drugs.
Keywords
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References
Abe K, Shimokawa H et al (2004) Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 94(3):385–393
Abenhaim L, Moride Y et al (1996) Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 335(9):609–616
Arcot SS, Fagerland JA et al (1995) Basic fibroblast growth factor alterations during development of monocrotaline-induced pulmonary hypertension in rats. Growth Factors 12(2):121–130
Balasubramaniam V, Le Cras TD et al (2003) Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 284(5):L826–L833
Baudhuin LM, Jiang Y et al (2004) S1P3-mediated Akt activation and cross-talk with platelet-derived growth factor receptor (PDGFR). FASEB J 18(2):341–343
Benezra M, Vlodavsky I et al (1993) Thrombin-induced release of active basic fibroblast growth factor-heparan sulfate complexes from subendothelial extracellular matrix. Blood 81(12):3324–3331
Benisty JI, McLaughlin VV et al (2004) Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 126(4):1255–1261
Berk BC (2001) Vascular smooth muscle growth: autocrine growth mechanisms. Physiol Rev 81(3):999–1030
Blanpain C, Le Poul E et al (2003) Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc Res 60(3):518–528
Bonnet S, Michelakis ED et al (2006) 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(22):2630–2641
Brenner B, Harney JT et al (2007) Plasma serotonin levels and the platelet serotonin transporter. J Neurochem 102(1):206–215
Brenot F, Herve P et al (1993) Primary pulmonary hypertension and fenfluramine use. Br Heart J 70(6):537–541
Breuer J, Georgaraki A et al (1996) Increased turnover of serotonin in children with pulmonary hypertension secondary to congenital heart disease. Pediatr Cardiol 17(4):214–219
Buczek-Thomas JA, Nugent MA (1999) Elastase-mediated release of heparan sulfate proteoglycans from pulmonary fibroblast cultures. A mechanism for basic fibroblast growth factor (bFGF) release and attenuation of bfgf binding following elastase-induced injury. J Biol Chem 274(35):25167–25172
Callebert J, Esteve JM et al (2006) Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice. J Pharmacol Exp Ther 317(2):724–731
Campbell AI, Zhao Y et al (2001) Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation 104(18):2242–2248
Christ G, Graf S et al (2001) Impairment of the plasmin activation system in primary pulmonary hypertension: evidence for gender differences. Thromb Haemost 86(2):557–562
Christou H, Yoshida A et al (1998) Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 18(6):768–776
Ciccolini F, Svendsen CN (1998) Fibroblast growth factor 2 (FGF-2) promotes acquisition of epidermal growth factor (EGF) responsiveness in mouse striatal precursor cells: identification of neural precursors responding to both EGF and FGF-2. J Neurosci 18(19):7869–7880
Ciuclan L, Bonneau O et al (2011) A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 184(10):1171–1182
Cogolludo A, Moreno L et al (2006) Serotonin inhibits voltage-gated K+ currents in pulmonary artery smooth muscle cells: role of 5-HT2A receptors, caveolin-1, and KV1.5 channel internalization. Circ Res 98(7):931–938
Cool CD, Kennedy D et al (1997) Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 28(4):434–442
Courboulin A, Paulin R et al (2011) Role for miR-204 in human pulmonary arterial hypertension. J Exp Med 208(3):535–548
Courboulin A, Barrier M et al (2012) Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH. Eur Respir J 40(3):618–629
Cowan KN, Jones PL et al (1999) 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 84(10):1223–1233
Cowan KN, Heilbut A et al (2000a) Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 6(6):698–702
Cowan KN, Jones PL et al (2000b) Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 105(1):21–34
Dahal BK, Cornitescu T et al (2010) Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med 181(2):158–167
Dann SG, Selvaraj A et al (2007) mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 13(6):252–259
de Man FS, Tu L et al (2012) Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 186(8):780–789
Dimmeler S, Zeiher AM (1999) Nitric oxide-an endothelial cell survival factor. Cell Death Differ 6(10):964–968
Ding W, Shi W et al (2007) Sprouty2 downregulation plays a pivotal role in mediating crosstalk between TGF-beta1 signaling and EGF as well as FGF receptor tyrosine kinase-ERK pathways in mesenchymal cells. J Cell Physiol 212(3):796–806
Dorfmuller P, Perros F et al (2003) Inflammation in pulmonary arterial hypertension. Eur Respir J 22(2):358–363
Douglas JG, Munro JF et al (1981) Pulmonary hypertension and fenfluramine. Br Med J (Clin Res Ed) 283(6296):881–883
Du L, Sullivan CC et al (2003) Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 348(6):500–509
Dumitrascu R, Kulcke C et al (2011) Terguride ameliorates monocrotaline induced pulmonary hypertension in rats. Eur Respir J 37(5):1104–1118
Eddahibi S, Raffestin B et al (1997) Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol 272(3 Pt 2):H1173–H1181
Eddahibi S, Raffestin B et al (1998) Effect of dexfenfluramine treatment in rats exposed to acute and chronic hypoxia. Am J Respir Crit Care Med 157(4 Pt 1):1111–1119
Eddahibi S, Hanoun N et al (2000a) Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 105(11):1555–1562
Eddahibi S, Humbert M et al (2000b) Imbalance between platelet vascular endothelial growth factor and platelet-derived growth factor in pulmonary hypertension. Effect of prostacyclin therapy. Am J Respir Crit Care Med 162(4 Pt 1):1493–1499
Eddahibi S, Humbert M et al (2001) Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 108(8):1141–1150
Eddahibi S, Humbert M et al (2002) Hyperplasia of pulmonary artery smooth muscle cells is causally related to overexpression of the serotonin transporter in primary pulmonary hypertension. Chest 121(3 Suppl):97S–98S
Eddahibi S, Guignabert C et al (2006) Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Circulation 113(15):1857–1864
Fagan KA, Oka M et al (2004) Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol 287(4):L656–L664
Fischer P, Hilfiker-Kleiner D (2007) Survival pathways in hypertrophy and heart failure: the gp130-STAT axis. Basic Res Cardiol 102(5):393–411
Foletta VC, Lim MA et al (2003) Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J Cell Biol 162(6):1089–1098
Frishman WH, Huberfeld S et al (1995) Serotonin and serotonin antagonism in cardiovascular and non-cardiovascular disease. J Clin Pharmacol 35(6):541–572
Garcia-Cao I, Song MS et al (2012) Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell 149(1):49–62
Gary-Bobo G, Houssaini A et al (2010) Effects of HIV protease inhibitors on progression of monocrotaline- and hypoxia-induced pulmonary hypertension in rats. Circulation 122(19):1937–1947
Geiger R, Berger RM et al (2000) Enhanced expression of vascular endothelial growth factor in pulmonary plexogenic arteriopathy due to congenital heart disease. J Pathol 191(2):202–207
George SJ, Johnson JL et al (2001) Plasmin-mediated fibroblast growth factor-2 mobilisation supports smooth muscle cell proliferation in human saphenous vein. J Vasc Res 38(5):492–501
George J, Sun J et al (2012) Transgenic expression of human matrix metalloproteinase-1 attenuates pulmonary arterial hypertension in mice. Clin Sci (Lond) 122(2):83–92
Gerasimovskaya EV, Tucker DA et al (2005) Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced pulmonary artery adventitial fibroblast proliferation. J Appl Physiol 98(2):722–731
Giannelli G, Falk-Marzillier J et al (1997) Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277(5323):225–228
Gilboa L, Nohe A et al (2000) Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell 11(3):1023–1035
Goda N, Kanai M (2012) Hypoxia-inducible factors and their roles in energy metabolism. Int J Hematol 95(5):457–463
Goncalves LM (1998) Fibroblast growth factor-mediated angiogenesis for the treatment of ischemia. Lessons learned from experimental models and early human experience. Rev Port Cardiol 17(Suppl 2):II11–II20
Grouf JL, Throm AM et al (2007) Differential effects of EGF and TGF-beta1 on fibroblast activity in fibrin-based tissue equivalents. Tissue Eng 13(4):799–807
Guignabert C (2011) Interplay between serotonin transporter signaling and voltage-gated potassium channel (Kv) 1.5 expression. In: Sulica R, Preston I (eds) Pulmonary hypertension – from bench research to clinical challenges. InTech Europe Rijeka, Croatia, pp 49–66
Guignabert C, Raffestin B et al (2005) Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 111(21):2812–2819
Guignabert C, Izikki M et al (2006) Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension. Circ Res 98(10):1323–1330
Guignabert C, Alvira CM et al (2009a) Tie2-mediated loss of peroxisome proliferator-activated receptor-gamma in mice causes PDGF receptor-beta-dependent pulmonary arterial muscularization. Am J Physiol Lung Cell Mol Physiol 297(6):L1082–L1090
Guignabert C, Tu L et al (2009b) Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. FASEB J 23(12):4135–4147
Guilluy C, Sauzeau V et al (2005) Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension. Br J Pharmacol 146(7):1010–1018
Guilluy C, Rolli-Derkinderen M et al (2007) Transglutaminase-dependent RhoA activation and depletion by serotonin in vascular smooth muscle cells. J Biol Chem 282(5):2918–2928
Guilluy C, Eddahibi S et al (2009) RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med 179(12):1151–1158
Guo L, Qiu Z et al (2012) The microRNA-328 regulates hypoxic pulmonary hypertension by targeting at insulin growth factor 1 receptor and L-type calcium channel-alpha1C. Hypertension 59(5):1006–1013
Gurtner HP (1985) Aminorex and pulmonary hypertension. A review. Cor Vasa 27(2–3):160–171
He H, Venema VJ et al (1999) Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 274(35):25130–25135
Herrlich A, Daub H et al (1998) Ligand-independent activation of platelet-derived growth factor receptor is a necessary intermediate in lysophosphatidic, acid-stimulated mitogenic activity in L cells. Proc Natl Acad Sci USA 95(15):8985–8990
Herve P, Drouet L et al (1990) Primary pulmonary hypertension in a patient with a familial platelet storage pool disease: role of serotonin. Am J Med 89(1):117–120
Herve P, Launay JM et al (1995) Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99(3):249–254
Hiramine K, Sata N et al (2011) Hepatocyte growth factor improves the survival of rats with pulmonary arterial hypertension via the amelioration of pulmonary hemodynamics. Int J Mol Med 27(4):497–502
Hironaka E, Hongo M et al (2003) Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res 60(3):692–699
Hirose S, Hosoda Y et al (2000) Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension. Pathol Int 50(6):472–479
Huber K, Beckmann R et al (1994) Fibrinogen, t-PA, and PAI-1 plasma levels in patients with pulmonary hypertension. Am J Respir Crit Care Med 150(4):929–933
Huertas A, Tu L et al (2012) Leptin and regulatory T lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J 40(4):895–904
Humbert M, Monti G et al (1995) Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 151(5):1628–1631
Humbert M, Morrell NW et al (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43(12 Suppl S):13S–24S
Ieda M, Fukuda K et al (2004) Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. J Clin Invest 113(6):876–884
Ilkiw R, Todorovich-Hunter L et al (1989) SC-39026, a serine elastase inhibitor, prevents muscularization of peripheral arteries, suggesting a mechanism of monocrotaline-induced pulmonary hypertension in rats. Circ Res 64(4):814–825
Izikki M, Hanoun N et al (2007) Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 293(4):L1045–L1052
Izikki M, Guignabert C et al (2009) Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 119(3):512–523
Jiang GC, Tidwell K et al (2007) Neurotoxic potential of depleted uranium effects in primary cortical neuron cultures and in Caenorhabditis elegans. Toxicol Sci 99(2):553–565
Jones PL, Rabinovitch M (1996) Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ Res 79(6):1131–1142
Jones PL, Cowan KN et al (1997a) Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol 150(4):1349–1360
Jones PL, Crack J et al (1997b) 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 139(1):279–293
Jones PL, Jones FS et al (1999) Induction of vascular smooth muscle cell tenascin-C gene expression by denatured type I collagen is dependent upon a beta3 integrin-mediated mitogen-activated protein kinase pathway and a 122-base pair promoter element. J Cell Sci 112(Pt 4):435–445
Kasahara Y, Tuder RM et al (2000) Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 106(11):1311–1319
Katta S, Vadapalli S et al (2008) t-plasminogen activator inhibitor-1 polymorphism in idiopathic pulmonary arterial hypertension. Indian J Hum Genet 14(2):37–40
Keegan A, Morecroft I et al (2001) Contribution of the 5-HT(1B) receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT(1B)-receptor knockout mice and the 5-HT(1B/1D)-receptor antagonist GR127935. Circ Res 89(12):1231–1239
Kelvin DJ, Simard G et al (1989) FGF and EGF act synergistically to induce proliferation in BC3H1 myoblasts. J Cell Physiol 138(2):267–272
Kereveur A, Callebert J et al (2000) High plasma serotonin levels in primary pulmonary hypertension. Effect of long-term epoprostenol (prostacyclin) therapy. Arterioscler Thromb Vasc Biol 20(10):2233–2239
Kherbeck N, Tamby MC et al (2013) The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension. Clin Rev Allergy Immunol 44(1):31–38
Kim YM, Haghighat L et al (2011) Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions. Am J Pathol 179(3):1560–1572
Kimura K, Ieda M et al (2007) Cardiac sympathetic rejuvenation: a link between nerve function and cardiac hypertrophy. Circ Res 100(12):1755–1764
Kouri FM, Queisser MA et al (2008) Plasminogen activator inhibitor type 1 inhibits smooth muscle cell proliferation in pulmonary arterial hypertension. Int J Biochem Cell Biol 40(9):1872–1882
Krymskaya VP, Goncharova EA (2009) PI3K/mTORC1 activation in hamartoma syndromes: therapeutic prospects. Cell Cycle 8(3):403–413
Krymskaya VP, Snow J et al (2011) mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia. FASEB J 25(6):1922–1933
Kwapiszewska G, Markart P et al (2012) PAR-2 inhibition reverses experimental pulmonary hypertension. Circ Res 110(9):1179–1191
Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122(Pt 20):3589–3594
Laudi S, Steudel W et al (2007) Comparison of lung proteome profiles in two rodent models of pulmonary arterial hypertension. Proteomics 7(14):2469–2478
Launay JM, Herve P et al (2002) Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 8(10):1129–1135
Launay JM, Schneider B et al (2006) Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells. FASEB J 20(11):1843–1854
Lawrie A, Spiekerkoetter E et al (2005) Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circ Res 97(3):227–235
Le Cras TD, Hardie WD et al (2003) Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-alpha. Am J Physiol Lung Cell Mol Physiol 285(5):L1046–L1054
Lee YS, Byun J et al (2005) Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective tissue growth factor expression in the lung. Exp Mol Med 37(1):27–35
Lepetit H, Eddahibi S et al (2005) Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J 25(5):834–842
Li P, Oparil S et al (2003) Fibroblast growth factor mediates hypoxia-induced endothelin – a receptor expression in lung artery smooth muscle cells. J Appl Physiol 95(2):643–651, discussion 863
Long L, MacLean MR et al (2006) Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 98(6):818–827
Loogen F, Worth H et al (1985) Long-term follow-up of pulmonary hypertension in patients with and without anorectic drug intake. Cor Vasa 27(2–3):111–124
Louzier V, Raffestin B et al (2003) Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 284(6):L926–L937
Ma W, Han W et al (2011) Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease. J Clin Invest 121(11):4548–4566
MacLean MR, Deuchar GA et al (2004) Overexpression of the 5-hydroxytryptamine transporter gene: effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension. Circulation 109(17):2150–2155
Marcos E, Adnot S et al (2003) Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am J Respir Crit Care Med 168(4):487–493
Marcos E, Fadel E et al (2004) Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res 94(9):1263–1270
Marcos E, Fadel E et al (2005) Serotonin transporter and receptors in various forms of human pulmonary hypertension. Chest 128(6 Suppl):552S–553S
Maruyama K, Ye CL et al (1991) Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity. Am J Physiol 261(6 Pt 2):H1716–H1726
Masri FA, Xu W et al (2007) Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 293(3):L548–L554
Mathew R, Huang J et al (2004) Disruption of endothelial-cell caveolin-1alpha/raft scaffolding during development of monocrotaline-induced pulmonary hypertension. Circulation 110(11):1499–1506
Matsunaga S, Okigaki M et al (2009) Endothelium-targeted overexpression of constitutively active FGF receptor induces cardioprotection in mice myocardial infarction. J Mol Cell Cardiol 46(5):663–673
McMurtry MS, Bonnet S et al (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95(8):830–840
Merklinger SL, Jones PL et al (2005) Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112(3):423–431
Michelakis ED, McMurtry MS et al (2002) Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 105(2):244–250
Mitani Y, Ueda M et al (1999) Mast cell chymase in pulmonary hypertension. Thorax 54(1):88–90
Morecroft I, Heeley RP et al (1999) 5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor. Br J Pharmacol 128(3):730–734
Morecroft I, Loughlin L et al (2005) Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries. J Pharmacol Exp Ther 313(2):539–548
Morrell NW, Adnot S et al (2009) Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 54(1 Suppl):S20–S31
Murillo MM, del Castillo G et al (2005) Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes. Oncogene 24(28):4580–4587
Nagaoka T, Morio Y et al (2004) Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 287(4):L665–L672
Nagaoka T, Fagan KA et al (2005) Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 171(5):494–499
Nagy JA, Dvorak AM et al (2012) Vascular hyperpermeability, angiogenesis, and stroma generation. Cold Spring Harb Perspect Med 2(2):a006544
Nakagawa O, Fujisawa K et al (1996) ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 392(2):189–193
Nasim MT, Ogo T et al (2012) BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH. Hum Mol Genet 21(11):2548–2558
Natali D, Girerd B et al (2011) Pulmonary arterial hypertension in a patient with Cowden syndrome and anorexigen exposure. Chest 140(4):1066–1068
Nilsson O, Ericson LE et al (1985) Subcellular localization of serotonin immunoreactivity in rat enterochromaffin cells. Histochemistry 82(4):351–355
Nishimaki T, Aotsuka S et al (1999) Immunological analysis of pulmonary hypertension in connective tissue diseases. J Rheumatol 26(11):2357–2362
O’Callaghan DS, Savale L et al (2011) Treatment of pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol 8(9):526–538
Ogawa A, Firth AL et al (2012) PDGF enhances store-operated Ca2+ entry by upregulating STIM1/Orai1 via activation of Akt/mTOR in human pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 302(2):C405–C411
Ono M, Sawa Y et al (2004a) Gene transfer of hepatocyte growth factor with prostacyclin synthase in severe pulmonary hypertension of rats. Eur J Cardiothorac Surg 26(6):1092–1097
Ono M, Sawa Y et al (2004b) Hepatocyte growth factor suppresses vascular medial hyperplasia and matrix accumulation in advanced pulmonary hypertension of rats. Circulation 110(18):2896–2902
Park JS, Kim JY et al (2000) Epidermal growth factor (EGF) antagonizes transforming growth factor (TGF)-beta1-induced collagen lattice contraction by human skin fibroblasts. Biol Pharm Bull 23(12):1517–1520
Partovian C, Adnot S et al (1998) Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertension. Am J Physiol 275(6 Pt 2):H1948–H1956
Partovian C, Adnot S et al (2000) Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol 23(6):762–771
Paulin R, Courboulin A et al (2011a) Signal transducers and activators of transcription-3/pim1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension. Circulation 123(11):1205–1215
Paulin R, Meloche J et al (2011b) Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 301(5):H1798–H1809
Pendergrass SA, Hayes E et al (2010) Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS One 5(8):e12106
Perros F, Montani D et al (2008) Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 178(1):81–88
Perros F, Dorfmuller P et al (2012) Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 185(3):311–321
Price LC, Wort SJ et al (2012) Inflammation in pulmonary arterial hypertension. Chest 141(1):210–221
Puzio-Kuter AM (2011) The role of p53 in metabolic regulation. Genes Cancer 2(4):385–391
Quinn TP, Schlueter M et al (2002) Cyclic mechanical stretch induces VEGF and FGF-2 expression in pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 282(5):L897–L903
Rabinovitch M (1999) EVE and beyond, retro and prospective insights. Am J Physiol 277(1 Pt 1):L5–L12
Rabinovitch M (2001) Pathobiology of pulmonary hypertension. Extracellular matrix. Clin Chest Med 22(3):433–449, viii
Rabinovitch M (2005) Cellular and molecular pathobiology of pulmonary hypertension conference summary. Chest 128(6 Suppl):642S–646S
Ravi Y, Selvendiran K et al (2011) Dysregulation of PTEN in cardiopulmonary vascular remodeling induced by pulmonary hypertension. Cell Biochem Biophys. doi:10.1007/s12013-011-9332-z
Ray L, Mathieu M et al (2008) Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure. Exp Physiol 93(3):434–442
Ren W, Watts SW et al (2011) Serotonin transporter interacts with the PDGFbeta receptor in PDGF-BB-induced signaling and mitogenesis in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 300(3):L486–L497
Reynolds AM, Holmes MD et al (2012) Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. Eur Respir J 39(2):329–343
Rondelet B, Kerbaul F et al (2003) Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension. Circulation 107(9):1329–1335
Saito Y, Berk BC (2001) Transactivation: a novel signaling pathway from angiotensin II to tyrosine kinase receptors. J Mol Cell Cardiol 33(1):3–7
Sands M, Howell K et al (2011) Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung. Respir Res 12:17
Sato K, Webb S et al (1992) Factors influencing the idiopathic development of pulmonary hypertension in the fawn hooded rat. Am Rev Respir Dis 145(4 Pt 1):793–797
Savale L, Tu L et al (2009) Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 10:6
Schermuly RT, Dony E et al (2005) Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115(10):2811–2821
Shang M, Koshikawa N et al (2001) The LG3 module of laminin-5 harbors a binding site for integrin alpha3beta1 that promotes cell adhesion, spreading, and migration. J Biol Chem 276(35):33045–33053
Soon E, Holmes AM et al (2010) Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122(9):920–927
Steiner MK, Syrkina OL et al (2009) Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 104(2):236–244, 228p following 244
Sullivan CC, Du L et al (2003) Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci USA 100(21):12331–12336
Sundaram N, Tailor A et al (2010) High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension. Blood 116(1):109–112
Sutendra G, Bonnet S et al (2010) Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci Transl Med 2(44):44ra58
Takahashi H, Goto N et al (2006) Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 290(3):L450–L458
Tamby MC, Chanseaud Y et al (2005) Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 60(9):765–772
Tamosiuniene R, Tian W et al (2011) Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res 109(8):867–879
Tanabe Y, Saito M et al (2000) Mechanical stretch augments PDGF receptor beta expression and protein tyrosine phosphorylation in pulmonary artery tissue and smooth muscle cells. Mol Cell Biochem 215(1–2):103–113
Taraseviciene-Stewart L, Kasahara Y et al (2001) Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 15(2):427–438
Teichert-Kuliszewska K, Kutryk MJ et al (2006) Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res 98(2):209–217
Terrier B, Tamby MC et al (2008) Identification of target antigens of antifibroblast antibodies in pulmonary arterial hypertension. Am J Respir Crit Care Med 177(10):1128–1134
Thompson K, Rabinovitch M (1996) Exogenous leukocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular-matrix bound basic fibroblast growth factor. J Cell Physiol 166(3):495–505
Tian J, Smith A et al (2009) Effect of PPARgamma inhibition on pulmonary endothelial cell gene expression: gene profiling in pulmonary hypertension. Physiol Genomics 40(1):48–60
Tu L, Dewachter L et al (2011) Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension. Am J Respir Cell Mol Biol 45(2):311–322
Tu L, de Man FS et al (2012) A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodent. Am J Respir Crit Care Med 186(7):666–676
Tuder RM, Chacon M et al (2001) Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol 195(3):367–374
Uttamsingh S, Bao X et al (2008) Synergistic effect between EGF and TGF-beta1 in inducing oncogenic properties of intestinal epithelial cells. Oncogene 27(18):2626–2634
Vanhoutte PM (1991) Platelet-derived serotonin, the endothelium, and cardiovascular disease. J Cardiovasc Pharmacol 17(Suppl 5):S6–S12
Vieillard-Baron A, Frisdal E et al (2000) Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats. Circ Res 87(5):418–425
Vieillard-Baron A, Frisdal E et al (2003) Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer limits monocrotaline-induced pulmonary vascular remodeling in rats. Hum Gene Ther 14(9):861–869
Voelkel NF, Vandivier RW et al (2006) Vascular endothelial growth factor in the lung. Am J Physiol Lung Cell Mol Physiol 290(2):L209–L221
Wang Y, Han DD et al (2011) Downregulation of osteopontin is associated with fluoxetine amelioration of monocrotaline-induced pulmonary inflammation and vascular remodelling. Clin Exp Pharmacol Physiol 38(6):365–372
Wedgwood S, Devol JM et al (2007) Fibroblast growth factor-2 expression is altered in lambs with increased pulmonary blood flow and pulmonary hypertension. Pediatr Res 61(1):32–36
Wei L, Warburton R et al (2012) Serotonylated fibronectin is elevated in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 302(12):L1273–L1279
Wheeler-Jones C, Abu-Ghazaleh R et al (1997) Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen-activated protein kinase. FEBS Lett 420(1):28–32
Wullschleger S, Loewith R et al (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484
Xu J, Rodriguez D et al (2001) Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J Cell Biol 154(5):1069–1079
Xu W, Koeck T et al (2007) Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci USA 104(4):1342–1347
Yamboliev IA, Gerthoffer WT (2001) Modulatory role of ERK MAPK-caldesmon pathway in PDGF-stimulated migration of cultured pulmonary artery SMCs. Am J Physiol Cell Physiol 280(6):C1680–C1688
Yang X, Long L et al (2005) Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 96(10):1053–1063
Zaidi SH, You XM et al (2002) Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 105(4):516–521
Zhai FG, Zhang XH et al (2009) Fluoxetine protects against monocrotaline-induced pulmonary arterial hypertension: potential roles of induction of apoptosis and upregulation of Kv1.5 channels in rats. Clin Exp Pharmacol Physiol 36(8):850–856
Zhu SP, Mao ZF et al (2009) Continuous fluoxetine administration prevents recurrence of pulmonary arterial hypertension and prolongs survival in rats. Clin Exp Pharmacol Physiol 36(8):e1–e5
Acknowledgments
The authors thank Pr. Marc Humbert, Pr. Elie Fadel, Pr. Philippe Dartevelle and Pr. Gérald Simonneau for valuable discussions and suggestions.
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Tu, L., Guignabert, C. (2013). Emerging Molecular Targets for Anti-proliferative Strategies in Pulmonary Arterial Hypertension. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_17
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