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New Molecular Targets of Pulmonary Vascular Remodeling in Pulmonary Arterial HypertensionPulmonary Arterial Hypertension Molecular Targets: Importance of Endothelial Communication FREE TO VIEW

Christophe Guignabert, PhD; Ly Tu, PhD; Barbara Girerd, PhD; Nicolas Ricard, PhD; Alice Huertas, MD, PhD; David Montani, MD, PhD; Marc Humbert, MD, PhD
Author and Funding Information

From INSERM UMR_S 999 (Drs Guignabert, Tu, Girerd, Ricard, Huertas, Montani, and Humbert), LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Univ. Paris-Sud, School of Medicine (Drs Guignabert, Tu, Girerd, Ricard, Huertas, Montani, and Humbert), DHU Thorax Innovation, Kremlin-Bicêtre; and AP-HP (Drs Girerd, Huertas, Montani, and Humbert), Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, France.

CORRESPONDENCE TO: Marc Humbert, MD, PhD, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Service de Pneumologie, 78 rue du Général-Leclerc, 94275 Le Kremlin Bicêtre cedex, France; e-mail: marc.humbert@bct.aphp.fr


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Chest. 2015;147(2):529-537. doi:10.1378/chest.14-0862
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Pulmonary arterial hypertension (PAH) is a disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in mean pulmonary arterial pressure, resulting in a progressive functional decline despite current available therapeutic options. The fundamental pathogenetic mechanisms underlying this disorder include pulmonary vasoconstriction, in situ thrombosis, medial hypertrophy, and intimal proliferation, leading to occlusion of the small to mid-sized pulmonary arterioles and the formation of plexiform lesions. Several predisposing or promoting mechanisms that contribute to excessive pulmonary vascular remodeling in PAH have emerged, such as altered crosstalk between cells within the vascular wall, sustained inflammation and dysimmunity, inhibition of cell death, and excessive activation of signaling pathways, in addition to the impact of systemic hormones, local growth factors, cytokines, transcription factors, and germline mutations. Although the spectrum of therapeutic options for PAH has expanded in the last 20 years, available therapies remain essentially palliative. However, over the past decade, a better understanding of new key regulators of this irreversible pulmonary vascular remodeling has been obtained. This review examines the state-of-the-art potential new targets for innovative research in PAH, focusing on (1) the crosstalk between cells within the pulmonary vascular wall, with particular attention to the role played by dysfunctional endothelial cells; (2) aberrant inflammatory and immune responses; (3) the abnormal extracellular matrix function; and (4) altered BMPRII/KCNK3 signaling systems. A better understanding of novel pathways and therapeutic targets will help in the designing of new and more effective approaches for PAH treatment.

Figures in this Article

Pulmonary hypertension (PH) is a complex and multifactorial cardiopulmonary disorder characterized by a progressive sustained increase in mean pulmonary arterial pressure (mPAP), leading to right-sided heart failure and death. PH can result from precapillary (arterial) or postcapillary (venous) pathomechanisms. The current PH clinical classification gathers groups of PH that share similar hemodynamic criteria and types of pulmonary vascular lesions to optimize therapeutic approaches, predict patient outcomes, and facilitate research strategies.1

Group 1 PH corresponds to pulmonary arterial hypertension (PAH). PAH is characterized by precapillary PH (mPAP ≥ 25 mm Hg, with a normal pulmonary capillary wedge pressure ≤ 15 mm Hg) due to major pulmonary arterial remodeling. In the absence of specific treatments, patients have a mean survival of 2.8 years.1,2 Specific therapies that have been approved for use to manage PAH include agents that have important vasoactive effects, modulating abnormalities in three main pathobiologic pathways for PAH: endothelin (ET)-1, prostacyclin (PGI2), and nitric oxide (NO). However, these current therapeutic options only partially improve symptoms and survival, and lung transplantation remains an important treatment in eligible patients with severe PAH refractory to medical management.

Irreversible remodeling of the pulmonary vascular bed is the cause of increased mPAP in PAH and frequently leads to progressive functional decline in patients despite the available medical treatments. The increasing knowledge about PAH pathogenesis clearly underscores the importance of microenvironmental alterations and, in particular, of the crosstalk between pulmonary vascular-wall cells in PAH development and/or progression. Among these intercell communications, the crosstalk between dysfunctional endothelial cells (ECs) and the other components of the pulmonary vascular wall, such as smooth muscle cells (SMCs), myofibroblasts, and pericytes, or the circulating immune cells, represent a key feature of PAH pathogenesis.

This article reviews the current knowledge of the intrinsic abnormal properties of pulmonary ECs from patients with PAH and their functional effects on the different vascular-wall cell types. In addition, we profile the innovative research into novel pathways and therapeutic targets that may lead to the development of targeted agents for use in PAH.

Pulmonary vascular lesions occurring in patients with PAH (as well as in animal models of the disease) include, to varying degrees, abnormal muscularization of distal and medial precapillary arteries, loss of precapillary arteries, thickening of the pulmonary arteriolar wall with concentric or eccentric laminar lesions, neointimal formation, fibrinoid necrosis, and the formation of complex lesions commonly named “plexiform lesions.”3 Although different forms of PAH could reflect distinct pathomechanisms, current evidence strongly suggests that a common denominator underlying many of the established molecular and cellular elements is altered crosstalk between cells within the vascular wall (ie, SMCs, myofibroblasts, pericytes, and ECs) and also sustained inflammation and dysimmunity, altered energy metabolism, inhibition of cell death, and excessive activation of some growth factor-stimulated signaling pathways, in addition to the interaction of systemic hormones, local growth factors, cytokines, and transcription factors.

The understanding of the etiology of PAH continues to evolve, including many disease-predisposing and/or contributing factors, such as inflammation, pulmonary endothelial dysfunction, aberrant vascular-wall cell proliferation, and several gene mutations (Fig 1).36 Therefore, the molecular and cellular bases of the pulmonary vascular remodeling associated with PAH needs clarification to better understand the disease and to propose new, more adapted, and more powerful therapeutic tools.

Figure Jump LinkFigure 1 –  Current concepts of pulmonary arterial hypertension pathogenesis and innovative strategies to prevent and/or limit pulmonary vascular remodeling. 5-HT = serotonin; AngII = angiotensin II; Bcl2 = B-cell lymphoma 2; Bcl-XL = B-cell lymphoma-extra large; BMPRII = bone morphogenetic protein receptor II; Ca2+ = calcium ion; CCL = chemokine ligand; EGF = epidermal growth factor; ET-1 = endothelin-1; FGF-2 = fibroblast growth factor-2; Kv = voltage-gated K+ channel; Mcl-1 = myeloid cell leukemia sequence 1; MCP = monocyte chemoattractant protein; NO = nitric oxide; PDGF = platelet-derived growth factor; PGI2 = prostacyclin; PH = pulmonary hypertension; SMC = smooth muscle cell; TASK = TWIK-related acid-sensitive K+ channel; TH = T helper; Treg = regulatory T lymphocyte; TRPC = transient receptor potential, canonical; vWF = von Willebrand factor.Grahic Jump Location

Clinical and preclinical studies strongly support the idea that the aberrant local microenvironment in the pulmonary vascular wall plays a critical role in either initiation and/or perpetuation of the characteristic progressive pulmonary arterial obstruction in PAH. Investigations provide evidence that the pulmonary endothelium in PAH is a critical local source of several key mediators for vascular remodeling, including growth factors (fibroblast growth factor [FGF]-2, serotonin [5-HT], angiotensin II [AngII]), and vasoactive peptides (NO, PGI2, ET-1), cytokines (IL-1, IL-6, macrophage migration inhibitory factor [MIF]), and chemokines (monocyte chemoattractant protein [MCP]-1), adipokines (leptin).713 Indeed, our group has underscored altered crosstalk between cells within the vascular wall and, more specifically, between pulmonary ECs and pulmonary arterial SMCs,8,1117 pulmonary ECs with pulmonary pericytes,7 and pulmonary ECs with local immune cells6,9 (Fig 2).

Figure Jump LinkFigure 2 –  Altered crosstalk between cells within the remodeled pulmonary vascular wall of patients with pulmonary hypertension (PAH) and molecular targets that may lead to the development of targeted agents. In PAH, evidence supports the notion of aberrant interactions between pulmonary endothelial cells with (1) pulmonary arterial smooth muscle cells, (2) pulmonary pericytes, and (3) local immune cells. A better understanding of cellular miscommunications may support development of novel therapeutic strategies. Akt = protein kinase B; CD = clusters of differentiation; GM-CSF = granulocyte-macrophage colony-stimulating factor; HIF = hypoxia-inducible factor; JNK = c-Jun N-terminal kinase; MIF = macrophage migration inhibitory factor; MMP = matrix metalloproteinase; mTOR = mammalian target of rapamycin; NF-κB = nuclear factor-κB; Nox = NADPH oxidase; Nrf2 = NF-Es-related factor 2; PTEN = phosphatase and tensin homolog on chromosome ten; ROCK = Rho-associated protein kinase; SERCA = sarcoplasmic/endoplasmic reticulum calcium ATPase; SOD = superoxide dismutase. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Paracrine overproduction of ET-1, 5-HT,13 AngII,8,18 and FGF-210,11,17 contributes to an increased pulmonary vascular cell proliferation, survival, migration, and differentiation. In accordance with these observations, preclinical studies have reported the benefits of inhibiting the serotoninergic, endothelin, and renin-angiotensin-aldosterone systems, or the aberrant growth-factor signaling pathways in disease models using inhibitors with improvements in pulmonary hemodynamics, pulmonary vascular remodeling, and survival.19 We have also shown that dysfunctional pulmonary ECs from patients with idiopathic PAH, through an aberrant release of FGF-2 and IL-6, contribute to increased pericyte coverage of distal pulmonary arteries in PAH, an abnormality that is a potential source of smooth muscle-like cells.7 Indeed, we have reported that transforming growth factor (TGF)-β1, which we shown to be overactivated in pulmonary arterial walls in PAH, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells. Thus, we suspect that neutralization of FGF-2, IL-6, and TGF-β1 may prevent pericyte recruitment and differentiation, and thus may be beneficial against the progression of PAH.7 Multiple lines of evidence also suggest that advanced pulmonary vascular remodeling in PAH may be reversed by approaches that address specific inflammatory and immune processes: Inflammatory cells and mediators are present and/or released in pulmonary vascular lesions and some of these factors correlate with a worse clinical outcome in patients with PAH and may serve as biomarkers of disease progression (ie, IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12, IL-13, and tumor necrosis factor-α).6,2024 Some, such as IL-1β and tumor necrosis factor-α, have been related to an accumulation of fibronectin or to the proliferation of pulmonary artery SMCs and pericytes.7,25,26

Further studies are needed to investigate abnormalities in EC communications with other pulmonary vascular cells (SMCs, myofibroblasts, and pericytes) and immune cells such as regulatory T lymphocytes (Tregs) and test the efficacy of the restoration of a functional cellular crosstalk between these cells. Identification of these factors could lead to novel therapeutic targets. Data from our group27 have demonstrated that increased production of MIF and overexpression of its selective endothelial receptor CD74 represent a key signaling axis at the crossroad of inflammation and endothelial dysfunction, and thus may play an important role in the pathogenesis of PAH. MIF is a critical upstream inflammatory mediator with pleiotropic actions partly explained by its binding to the extracellular domain of CD74. In EC, signal transduction from CD74/MIF can lead to the activation of Src-family kinase, MAPK/ERK, PI3K/Akt, and nuclear factor-κB pathways, and to cell survival by increasing two key antiapoptotic factors—BCL2 and BCL-xL—observed in PAH lesions,28 and by inhibiting p53. Furthermore, MIF can bind to CXCR2 and CXCR4, lead to the proliferation of pulmonary artery SMCs, and contribute to hypoxic PH,2932 and CD74 is known to interact with angiotensin AT1-receptor and NO synthase.33,34 Besides the MIF/CD74 axis, recent unpublished data from our group also strongly support that attenuation of the exaggerated secretion of pulmonary endothelial-derived leptin may represent a way to attenuate pulmonary artery SMC proliferation and Treg impairment and prevents the severity of chronic hypoxia-induced PH.

During the last few years, greater attention has focused on the inflammatory pattern seen in plexiform lesions and other intimal lesions in PAH, and novel molecular targets are emerging.6,24 As previously discussed, circulating levels of certain cytokines and chemokines are abnormally elevated and some have been reported to correlate with a worse clinical outcome in patients with PAH.7,25,26 Histopathologically, pulmonary vascular lesions occurring in patients with PAH, as well as in animal models of PH, are characterized by varying degrees of perivascular inflammatory infiltrates composed of T and B lymphocytes, macrophages, dendritic cells, and mast cells. Correlations have been described of the average perivascular inflammation score with intima plus media and adventitia thickness, respectively, and with pulmonary hemodynamic parameters, supporting a role for perivascular inflammation in the processes of pulmonary vascular remodeling.35 In addition, phenotypic alterations and functional defects in cytotoxic T and natural killer cells are linked to human PAH and experimental PH, as well as pulmonary veno-occlusive disease.36,37 A study from our group has also provided evidence for lymphoid neogenesis in lungs from patients with idiopathic PAH,38 a hallmark of autoimmune diseases.

Although elements of inflammation seem to be present in remodeled pulmonary arteries of patients displaying idiopathic and associated PAH, the specific role of immune cells in the development and/or maintenance of obstructive pulmonary arterial lesions remains unclear.6,24 However, the close interplay between inflammation and metabolism can represent one potential explanation. Several elements suggest that a Warburg phenotype (a chronic shift in energy production from mitochondrial oxidative phosphorylation to glycolysis) of pulmonary vascular cells is present and may participate to the pathogenesis of the disease. Indeed, restitution of oxidative metabolism with the use of dichloroacetate has been shown to be efficient in several animal models of PH.16,39,40 Similarly, the inhibition of mitochondrial fatty-acid oxidation also has been found to be beneficial against this metabolic shift and to limit the perpetuation of this characteristic progressive pulmonary vascular obstruction in PH.41 In addition to interrelationships between inflammation and metabolism, a recent study has obtained evidence that macrophage granulocyte-macrophage colony-stimulating factor and LTB4 signaling pathways play critical role in promoting PAH vascular remodeling.42 Indeed, CD68+ macrophages are prominent in advanced obliterative plexiform lesions observed in experimental and clinical PH,4349 and macrophage depletion or inactivation prevents PH in several model systems, including experimentally induced hypoxic PH and portopulmonary hypertension.42,46 In addition, recent data strongly support the idea that the leptin signaling system may represent a way to attenuate Treg impairment and prevent the severity of chronic hypoxia-induced PH.9 However, given the complexity of these biologic processes, additional insights into immune cells and key inflammatory mediators are a prerequisite for a better understanding of disease immunopathology and, in turn, development of novel therapeutic strategies. Currently, a randomized clinical trial testing the safety and efficacy of the monoclonal antibody anti-CD20, a B-lymphocyte protein, is in phase 2 studies in patients with PAH with systemic sclerosis.50

Qualitative and quantitative changes in the extracellular matrix (ECM) contribute to the aberrant local microenvironment in the remodeled pulmonary vascular wall in PAH by creating a permissive pericellular/extracellular environment for cell proliferation, survival, and migration. Inappropriate ECM remodeling can promote local pulmonary vascular remodeling in three ways: (1) the generation of fragments of ECM components known to directly modulate proliferation, migration, and protease activation; (2) the excessive release of growth factors and various molecules that are encrypted in the ECM; and (3) the exposure of functionally important cryptic sites in collagens, laminins, elastin, or fibronectin.19 In PAH, evidence supports the notion of an imbalance between proteases and protease inhibitors that could promote pulmonary vascular remodeling, more specifically in the elastase,51,52 matrix metalloproteinase (MMP),53,54 chymase,55 tryptase,56 and in the urokinase-type plasminogen activator plasmin system or the tissue-type plasminogen activator plasmin system.5760 The preclinical efficacies of various serine elastase and MMP inhibitors in experimental models of PH have been obtained.6166 Collectively, these findings support the idea that restoration of an appropriate balance between ECM synthesis and degradation in PAH may represent another strategy to prevent and/or reverse vascular remodeling processes.

BMPR2 and KCNK3 are two predisposing genes for heritable PAH that encode for a type 2 receptor member (bone morphogenetic protein receptor II [BMPRII]) of the TGF-β superfamily of cell-signaling molecules and the two-pore-domain potassium channels TASK-1, respectively. Heritable PAH due to BMPR2 or KCNK3 mutations is an autosomal dominant disease with incomplete penetrance.

BMPR2 mutations are the main predisposing risk factors for heritable PAH. Mutations in this gene are identified in approximately 75% of patients with PAH who display a familial PAH and in up to 25% of patients with apparently sporadic PAH. Moreover, it has been demonstrated that BMPRII expression is markedly reduced in pulmonary arteries of patients displaying idiopathic PAH without identified BMPR2 mutations.67 Ma and collaborators68 demonstrated the involvement of KCNK3 mutations in the pathophysiology of PAH. Indeed, mutations in this gene were identified in six unrelated patients with PAH (three patients displaying familial form of PAH out of 93 patients [3.2%] and three patients with sporadic PAH out of 230 patients [1.3%]).68 Thus, restoration of BMPRII and/or TASK1 expression/activity may represent future potential therapy to prevent and/or treat PAH.

Mutations identified in BMPR2 are spread throughout the gene with the exception of exon 13 and include missense mutations, nonsense mutations, splice defects, deletions, and duplications. mRNAs encoding for truncated proteins (due to a nonsense mutation or a large rearrangement not in reading frame) are rapidly degraded through the nonsense-mediated decay, an mRNA surveillance mechanism that detects and degrades transcripts containing premature termination codons. Thereby, the mechanism involved in the development of PAH is haplo-insufficiency. In contrast, a protein encoded by the mutated alleles (due to missense mutations or in frame deletions/duplications) is suspected to have a dominant negative effect on the wild-type BMPRII. Recently, Drake and colleagues69 found that treatment with ataluren, a small molecule that potently promotes read through of premature stop codons without affecting normal translational stop signals, can restore BMPRII expression in lung- or blood-derived cells from patients who are carriers of a nonsense mutation. In addition, ataluren treatment is known to attenuate the excessive pulmonary EC and SMC proliferation currently observed in patients with PAH. Taken with the fact that ataluren is already used in clinical trials in patients with cystic fibrosis who are carriers of truncating CFTR mutations,70 ataluren may represent a promising agent for future trials in patients carrying a nonsense mutation of BMPR2, representing approximately one-half of BMPR2 mutations.71,72 In addition, Frump and colleagues73 have reported that it is possible to restore TGF-β activity in lymphocytes derived from patients with PAH carrying an in-frame deletion of exon 2 of BMPR2 (nonsense-mediated decay negative mutation) by improving trafficking of the mutated protein using chemical chaperones. These authors speculated that chemical chaperones could have beneficial effect in all carriers of a missense BMPR2 mutation or in in-frame rearrangement, which affects the trafficking of the protein to the cell surface. Importantly, Spiekerkoetter and colleagues74 have recently demonstrated that a low dose of FK506 (tacrolimus) can reverse dysfunctional BMPRII signaling in pulmonary ECs from patients with idiopathic PAH and prevented experimental PH in different animal models (chronic hypoxic PH in mice with conditional BMPR2 deletion in ECs, monocrotaline-induced PH, and chronically hypoxic Su5416-treated rats).

To date, all identified KCNK3 mutations are missense mutations. All mutations are responsible for a loss of function of the potassium channel68 and, subsequently, a depolarization of the resting membrane potential, which could lead to vasoconstriction and pulmonary artery remodeling. Ma and colleagues68 demonstrated that it is possible to restore the TASK1 function using phospholipase A2 inhibitor. However, further studies are needed to better elucidate the role of the two-pore-domain potassium channels TASK-1 and its signaling pathway in PAH.

Finally, accumulating preclinical studies underscore the potential beneficial effects of various microRNAs (miRNAs) in the modulation of vascular inflammation, proliferation, and survival. It has been demonstrated that downregulation of miRNA-206 and miRNA-204 is associated with human pulmonary SMC proliferation and survival.75,76 Caruso and colleagues77 have shown an upregulation of miRNA-145 in lungs of patients with idiopathic PAH and heritable PAH compared with control subjects, and that anti-miRNA-145 can prevent the development of experimental PH in mice. Furthermore, Drake and colleagues78 demonstrated a direct link between BMPR2 and Smad9 mutations and the loss of miRNA-21, which can directly affect EC and SMC proliferation. Bertero and colleagues79 have also recently reported the critical role played by the miR-130/301 family that targets PPARγ and modulates apelin-miR-424/503-FGF2 signaling in ECs, and the STAT3-miR-204 signaling in SMCs. Therefore, targeting epigenetic modifiers and/or miRNAs could also represent potential future agents to modulate gene expression in patients.

In summary, important discoveries in the molecular and cellular bases of pulmonary vascular remodeling associated with PAH have been reported. This knowledge continues to accelerate, thanks to key methodological approaches and tools to study PAH/PH pathogenesis, and combining findings from in situ observations, in vitro studies with primary human cells, and various relevant PH animal models. Our improved understanding of additional pathways in this condition will presumably lead to the development of novel therapeutic strategies in the near future. However, there are significant challenges with these novel approaches, such as targeted drug delivery and the better understanding and evaluation of the overall risk-benefit ratio of the available and future targeted therapies in PAH. Last, it will be important to circumvent potential impacts of future therapeutic interventions on the adaptive response of myocardial hypertrophy and minimize the adverse effects of less-focused treatments.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

5-HT

serotonin

AngII

angiotensin II

BMPRII

bone morphogenetic protein receptor II

EC

endothelial cell

ECM

extracellular matrix

ET

endothelin

FGF

fibroblast growth factor

MCP

monocyte chemoattractant protein

MIF

migration inhibitory factor

miRNA

microRNA

MMP

matrix metalloproteinase

mPAP

mean pulmonary arterial pressure

NO

nitric oxide

PAH

pulmonary arterial hypertension

PGI2

prostacyclin

PH

pulmonary hypertension

SMC

smooth muscle cell

TGF

transforming growth factor

Treg

regulatory T lymphocyte

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Michelakis ED, McMurtry MS, Wu XC, et al. 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. 2002;105(2):244-250. [CrossRef] [PubMed]
 
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(8):830-840. [CrossRef] [PubMed]
 
Sutendra G, Bonnet S, Rochefort G, et al. Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci Transl Med. 2010;2(44):44ra58. [CrossRef] [PubMed]
 
Tian W, Jiang X, Tamosiuniene R, et al. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med. 2013;5(200):200ra117. [CrossRef] [PubMed]
 
Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J. 2003;22(2):358-363. [CrossRef] [PubMed]
 
Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144(2):275-285. [PubMed]
 
Savai R, Pullamsetti SS, Kolbe J, et al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(9):897-908. [CrossRef] [PubMed]
 
Thenappan T, Goel A, Marsboom G, et al. A central role for CD68(+) macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion. Am J Respir Crit Care Med. 2011;183(8):1080-1091. [CrossRef] [PubMed]
 
Overbeek MJ, Mouchaers KT, Niessen HM, et al. Characteristics of interstitial fibrosis and inflammatory cell infiltration in right ventricles of systemic sclerosis-associated pulmonary arterial hypertension. Int J Rheumatol. 2010;2010.
 
Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol. 2006;168(2):659-669. [CrossRef] [PubMed]
 
Vergadi E, Chang MS, Lee C, et al. Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. Circulation. 2011;123(18):1986-1995. [CrossRef] [PubMed]
 
National Institutes of Health Clinical Center. A randomized, double-blind, placebo-controlled, phase II multicenter trial of a monoclonal antibody to CD20 (Rituximab) for the treatment of systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). NCT01086540. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2010. http://clinicaltrials.gov/show/NCT01086540. Updated June 16, 2014.
 
Kim YM, Haghighat L, Spiekerkoetter E, et al. Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions. Am J Pathol. 2011;179(3):1560-1572. [CrossRef] [PubMed]
 
Rabinovitch M. EVE and beyond, retro and prospective insights. Am J Physiol. 1999;277(1 pt 1):L5-L12. [PubMed]
 
George J, Sun J, D’Armiento J. Transgenic expression of human matrix metalloproteinase-1 attenuates pulmonary arterial hypertension in mice. Clin Sci (Lond). 2012;122(2):83-92. [CrossRef] [PubMed]
 
Lepetit H, Eddahibi S, Fadel E, et al. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J. 2005;25(5):834-842. [CrossRef] [PubMed]
 
Mitani Y, Ueda M, Maruyama K, et al. Mast cell chymase in pulmonary hypertension. Thorax. 1999;54(1):88-90. [CrossRef] [PubMed]
 
Kwapiszewska G, Markart P, Dahal BK, et al. PAR-2 inhibition reverses experimental pulmonary hypertension. Circ Res. 2012;110(9):1179-1191. [CrossRef] [PubMed]
 
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(2):557-562. [PubMed]
 
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(4):929-933. [CrossRef] [PubMed]
 
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(2):37-40. [CrossRef] [PubMed]
 
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(9):1872-1882. [CrossRef] [PubMed]
 
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(6):698-702. [CrossRef] [PubMed]
 
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(4):814-825. [CrossRef] [PubMed]
 
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. [PubMed]
 
Vieillard-Baron A, Frisdal E, Eddahibi S, et al. Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats. Circ Res. 2000;87(5):418-425. [CrossRef] [PubMed]
 
Vieillard-Baron A, Frisdal E, Raffestin B, et al. Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer limits monocrotaline-induced pulmonary vascular remodeling in rats. Hum Gene Ther. 2003;14(9):861-869. [CrossRef] [PubMed]
 
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(4):516-521. [CrossRef] [PubMed]
 
Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002;105(14):1672-1678. [CrossRef] [PubMed]
 
Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369(4):351-361. [CrossRef] [PubMed]
 
Drake KM, Dunmore BJ, McNelly LN, Morrell NW, Aldred MA. Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2013;49(3):403-409. [CrossRef] [PubMed]
 
Kerem E, Hirawat S, Armoni S, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet. 2008;372(9640):719-727. [CrossRef] [PubMed]
 
Austin ED, Phillips JA, Cogan JD, et al. Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Respir Res. 2009;10:87. [CrossRef] [PubMed]
 
Girerd B, Montani D, Eyries M, et al. Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. Respir Res. 2010;11:73. [CrossRef] [PubMed]
 
Frump AL, Lowery JW, Hamid R, Austin ED, de Caestecker M. Abnormal trafficking of endogenously expressed BMPR2 mutant allelic products in patients with heritable pulmonary arterial hypertension. PLoS ONE. 2013;8(11):e80319. [CrossRef] [PubMed]
 
Spiekerkoetter E, Tian X, Cai J, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest. 2013;123(8):3600-3613. [CrossRef] [PubMed]
 
Meloche J, Pflieger A, Vaillancourt M, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014;129(7):786-797. [CrossRef] [PubMed]
 
Jalali S, Ramanathan GK, Parthasarathy PT, et al. Mir-206 regulates pulmonary artery smooth muscle cell proliferation and differentiation. PLoS ONE. 2012;7(10):e46808. [CrossRef] [PubMed]
 
Caruso P, Dempsie Y, Stevens HC, et al. A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res. 2012;111(3):290-300. [CrossRef] [PubMed]
 
Drake KM, Zygmunt D, Mavrakis L, et al. Altered microRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am J Respir Crit Care Med. 2011;184(12):1400-1408. [CrossRef] [PubMed]
 
Bertero T, Lu Y, Annis S, et al. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest. 2014;124(8):3514-3528. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Current concepts of pulmonary arterial hypertension pathogenesis and innovative strategies to prevent and/or limit pulmonary vascular remodeling. 5-HT = serotonin; AngII = angiotensin II; Bcl2 = B-cell lymphoma 2; Bcl-XL = B-cell lymphoma-extra large; BMPRII = bone morphogenetic protein receptor II; Ca2+ = calcium ion; CCL = chemokine ligand; EGF = epidermal growth factor; ET-1 = endothelin-1; FGF-2 = fibroblast growth factor-2; Kv = voltage-gated K+ channel; Mcl-1 = myeloid cell leukemia sequence 1; MCP = monocyte chemoattractant protein; NO = nitric oxide; PDGF = platelet-derived growth factor; PGI2 = prostacyclin; PH = pulmonary hypertension; SMC = smooth muscle cell; TASK = TWIK-related acid-sensitive K+ channel; TH = T helper; Treg = regulatory T lymphocyte; TRPC = transient receptor potential, canonical; vWF = von Willebrand factor.Grahic Jump Location
Figure Jump LinkFigure 2 –  Altered crosstalk between cells within the remodeled pulmonary vascular wall of patients with pulmonary hypertension (PAH) and molecular targets that may lead to the development of targeted agents. In PAH, evidence supports the notion of aberrant interactions between pulmonary endothelial cells with (1) pulmonary arterial smooth muscle cells, (2) pulmonary pericytes, and (3) local immune cells. A better understanding of cellular miscommunications may support development of novel therapeutic strategies. Akt = protein kinase B; CD = clusters of differentiation; GM-CSF = granulocyte-macrophage colony-stimulating factor; HIF = hypoxia-inducible factor; JNK = c-Jun N-terminal kinase; MIF = macrophage migration inhibitory factor; MMP = matrix metalloproteinase; mTOR = mammalian target of rapamycin; NF-κB = nuclear factor-κB; Nox = NADPH oxidase; Nrf2 = NF-Es-related factor 2; PTEN = phosphatase and tensin homolog on chromosome ten; ROCK = Rho-associated protein kinase; SERCA = sarcoplasmic/endoplasmic reticulum calcium ATPase; SOD = superoxide dismutase. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Tables

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Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115(1):165-175. [CrossRef] [PubMed]
 
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Jones PL, Cowan KN, Rabinovitch M. Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol. 1997;150(4):1349-1360. [PubMed]
 
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Zhang Y, Talwar A, Tsang D, et al. Macrophage migration inhibitory factor mediates hypoxia-induced pulmonary hypertension. Mol Med. 2012;18:215-223. [PubMed]
 
Zhang B, Luo Y, Liu ML, et al. Macrophage migration inhibitory factor contributes to hypoxic pulmonary vasoconstriction in rats. Microvasc Res. 2012;83(2):205-212. [CrossRef] [PubMed]
 
Zhang B, Shen M, Xu M, et al. Role of macrophage migration inhibitory factor in the proliferation of smooth muscle cell in pulmonary hypertension. Mediators Inflamm. 2012;2012:840737. [PubMed]
 
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Ormiston ML, Chang C, Long LL, et al. Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension. Circulation. 2012;126(9):1099-1109. [CrossRef] [PubMed]
 
Perros F, Cohen-Kaminsky S, Gambaryan N, et al. Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease. Am J Respir Crit Care Med. 2013;187(2):189-196. [CrossRef] [PubMed]
 
Perros F, Dorfmüller P, Montani D, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185(3):311-321. [CrossRef] [PubMed]
 
Michelakis ED, McMurtry MS, Wu XC, et al. 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. 2002;105(2):244-250. [CrossRef] [PubMed]
 
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(8):830-840. [CrossRef] [PubMed]
 
Sutendra G, Bonnet S, Rochefort G, et al. Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci Transl Med. 2010;2(44):44ra58. [CrossRef] [PubMed]
 
Tian W, Jiang X, Tamosiuniene R, et al. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med. 2013;5(200):200ra117. [CrossRef] [PubMed]
 
Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J. 2003;22(2):358-363. [CrossRef] [PubMed]
 
Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144(2):275-285. [PubMed]
 
Savai R, Pullamsetti SS, Kolbe J, et al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(9):897-908. [CrossRef] [PubMed]
 
Thenappan T, Goel A, Marsboom G, et al. A central role for CD68(+) macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion. Am J Respir Crit Care Med. 2011;183(8):1080-1091. [CrossRef] [PubMed]
 
Overbeek MJ, Mouchaers KT, Niessen HM, et al. Characteristics of interstitial fibrosis and inflammatory cell infiltration in right ventricles of systemic sclerosis-associated pulmonary arterial hypertension. Int J Rheumatol. 2010;2010.
 
Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol. 2006;168(2):659-669. [CrossRef] [PubMed]
 
Vergadi E, Chang MS, Lee C, et al. Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. Circulation. 2011;123(18):1986-1995. [CrossRef] [PubMed]
 
National Institutes of Health Clinical Center. A randomized, double-blind, placebo-controlled, phase II multicenter trial of a monoclonal antibody to CD20 (Rituximab) for the treatment of systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). NCT01086540. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2010. http://clinicaltrials.gov/show/NCT01086540. Updated June 16, 2014.
 
Kim YM, Haghighat L, Spiekerkoetter E, et al. Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions. Am J Pathol. 2011;179(3):1560-1572. [CrossRef] [PubMed]
 
Rabinovitch M. EVE and beyond, retro and prospective insights. Am J Physiol. 1999;277(1 pt 1):L5-L12. [PubMed]
 
George J, Sun J, D’Armiento J. Transgenic expression of human matrix metalloproteinase-1 attenuates pulmonary arterial hypertension in mice. Clin Sci (Lond). 2012;122(2):83-92. [CrossRef] [PubMed]
 
Lepetit H, Eddahibi S, Fadel E, et al. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J. 2005;25(5):834-842. [CrossRef] [PubMed]
 
Mitani Y, Ueda M, Maruyama K, et al. Mast cell chymase in pulmonary hypertension. Thorax. 1999;54(1):88-90. [CrossRef] [PubMed]
 
Kwapiszewska G, Markart P, Dahal BK, et al. PAR-2 inhibition reverses experimental pulmonary hypertension. Circ Res. 2012;110(9):1179-1191. [CrossRef] [PubMed]
 
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(2):557-562. [PubMed]
 
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(4):929-933. [CrossRef] [PubMed]
 
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(2):37-40. [CrossRef] [PubMed]
 
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(9):1872-1882. [CrossRef] [PubMed]
 
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(6):698-702. [CrossRef] [PubMed]
 
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(4):814-825. [CrossRef] [PubMed]
 
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. [PubMed]
 
Vieillard-Baron A, Frisdal E, Eddahibi S, et al. Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats. Circ Res. 2000;87(5):418-425. [CrossRef] [PubMed]
 
Vieillard-Baron A, Frisdal E, Raffestin B, et al. Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer limits monocrotaline-induced pulmonary vascular remodeling in rats. Hum Gene Ther. 2003;14(9):861-869. [CrossRef] [PubMed]
 
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(4):516-521. [CrossRef] [PubMed]
 
Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002;105(14):1672-1678. [CrossRef] [PubMed]
 
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