Cellular and molecular pathobiology of pulmonary arterial hypertension
Marc Humbert, MD, PhD*,*,
Nicholas W. Morrell, MD ,
Stephen L. Archer, MD ,
Kurt R. Stenmark, MD ,
Margaret R. MacLean, Bsc, PhD||,
Irene M. Lang, MD¶,
Brian W. Christman, MD,
E. Kenneth Weir, MD**,
Oliver Eickelberg, MD,
Norbert F. Voelkel, MD and
Marlene Rabinovitch, MD
* Service de Pneumologie et Réanimation Respiratoire, Centre des Maladies Vasculaires Pulmonaires, UPRES EA2705, Hôpital Antoine-Béclère, Université Paris-Sud, Clamart, France
Respiratory Medicine Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom
Vascular Biology Group and Pulmonary Hypertension Program, Department of Medicine (Cardiology), University of Alberta, Edmonton, Alberta, Canada
Development Lung Biology Research, University of Colorado Health Sciences Center, Denver, Colorado, USA
|| Division of Biomedical and Life Sciences, Institute of Biomedical and Life Sciences, Glasgow University, Glasgow, United Kingdom
¶ Department of Cardiology, University of Vienna, Vienna, Austria
Center for Lung Research, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
** Department of Medicine, Veterans Affairs Medical Center, Minneapolis, Minnesota, USA
Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, Colorado, USA
Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
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Figure 1 Consequences of pulmonary artery endothelial cell dysfunction on pulmonary artery smooth muscle cell tone and proliferation. Dysfunctional pulmonary artery endothelial cells (blue) have a decreased production of prostacyclin and nitric oxide, with an increased production of endothelin-1-promoting vasoconstriction and proliferation of pulmonary artery smooth muscle cells (red). cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; ET = endothelin; ETA = endothelin receptor A; ETB = endothelin receptor B; PDE5 = phosphodiesterase type 5.
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Figure 2 The balance of tone in pulmonary artery smooth muscle cells. Activity of voltage-gated potassium channels (Kv) in the smooth muscle cells of resistance pulmonary arteries affects vascular tone. In pulmonary arterial hypertension, the selective loss of Kv channels such as Kv1.5 leads to pulmonary artery smooth muscle cell depolarization, an increase in the intracellular calcium, and both vasoconstriction and cell proliferation.
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Figure 3 Serotonin receptors and transporter in pulmonary artery smooth muscle cells. The 5-hydroxytryptamine transporter (5-HTT) expression, activity, or both in pulmonary artery smooth muscle cells contribute to pulmonary vascular remodeling. The 5-HT1B mediates contraction in human pulmonary artery smooth muscle cells. A role for other 5-hydroxytryptamine (5-HT) receptors such as 5-HT2A and 5-HT2B has also been suggested.
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Figure 4 Potential roles of transforming growth factor-beta (TGF-ß) superfamily in vascular remodeling. The TGF-ß superfamily has diverse roles in a wide variety of physiological processes, including cell proliferation, differentiation, immunity, and inflammation. BMP = bone morphogenetic protein; GDF = growth and differentiation factor.
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Figure 5 Consequences of bone morphogenetic protein type-II receptor (BMPR2) mutations on signaling. Mutation analysis demonstrated that some BMPR2 mutations occur within exon 1 of the gene and would be predicted to cause nonsense-mediated messenger ribonucleic acid decay and failure to express the mutant protein, resulting in haploinsufficiency. Although this finding may be true for some mutations, it was also found in transfected cells that mutations involving the ligand binding or kinase domain of BMPR-II could exert a dominant negative effect on BMPR-II signaling via the Smad pathway. The mechanism by which BMPR-II mutants disrupt BMP/Smad signaling is heterogeneous, and mutation specific. Thus, substitution of cysteine residues within the ligand binding or kinase domain of BMPR-II leads to failure of trafficking of the mutant protein to the cell surface, which may interfere with wild-type receptor trafficking. In contrast, noncysteine mutations within the kinase domain reach the cell surface but fail to activate a Smad-responsive luciferase reporter gene. Interestingly, BMPR-II mutants with missense mutations involving the cytoplasmic tail reached the cell surface but were still capable of activating the Smad-responsive luciferase reporter gene. However, a feature common to all mutants transfected into normal mouse epithelial cells was ligand-independent activation of p38MAPK and enhanced serum-induced proliferation. Based on the results of these studies it was hypothesized that reduced cell-surface expression of BMPR-II favors activation of p38MAPK-dependent pro-proliferative pathways, while inhibiting Smad-dependent signaling in a mutation-specific manner. Thus, a feature common to all mutants is a gain of function involving p38MAPK activation.
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Figure 6 Schematic view of pulmonary arterial hypertension (PAH) pathophysiology. Pulmonary arterial hypertension has a multifactorial pathobiology, and it is unlikely that one factor or gene mutation will explain all forms and cases of PAH.
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