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      TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

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          Abstract

          Knowledge pertaining to the involvement of transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in pulmonary arterial hypertension (PAH) is continuously increasing. There is a growing understanding of the function of individual components involved in the pathway, but a clear synthesis of how these interact in PAH is currently lacking. Most of the focus has been on signaling downstream of BMPR2, but it is imperative to include the role of TGF-β signaling in PAH. This review gives a state of the art overview of disturbed signaling through the receptors of the TGF-β family with respect to vascular remodeling and cardiac effects as observed in PAH. Recent (pre)-clinical studies in which these two pathways were targeted will be discussed with an extended view on cardiovascular research fields outside of PAH, indicating novel future perspectives.

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          Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus

          Yigong Shi, Joan Massagué (2003)
          Article 0 comments Cited 431 times – based on 0 reviews     Review now
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            TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility.

            Bernhard Schmierer, Caroline Hill (2007)
            Ligands of the transforming growth factor-beta (TGFbeta) superfamily of growth factors initiate signal transduction through a bewildering complexity of ligand-receptor interactions. Signalling then converges to nuclear accumulation of transcriptionally active SMAD complexes and gives rise to a plethora of specific functional responses in both embryos and adult organisms. Current research is focused on the mechanisms that regulate SMAD activity to evoke cell-type-specific and context-dependent transcriptional programmes. An equally important challenge is understanding the functional role of signal strength and duration. How are these quantitative aspects of the extracellular signal regulated? How are they then sensed and interpreted, and how do they affect responses?
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              Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis

              Lutz Wollin, Eva Wex, Alexander Pautsch … (2015)
              Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix (ECM) proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and transforming growth factor-β are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials.
              Article 0 comments Cited 323 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 31 August 2018
                Publication date Collection: September 2018
                Volume: 19
                Issue: 9
                Electronic Location Identifier: 2585
                Affiliations
                [1 ]Department of Pulmonology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081HV Amsterdam, The Netherlands; n.rol@ 123456vumc.nl (N.R.); c.happe@ 123456vumc.nl (C.H.); hj.bogaard@ 123456vumc.nl (H.J.B.)
                [2 ]Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, 1081HV Amsterdam, The Netherlands
                [3 ]Department of Cell and Chemical Biology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands; k.b.kurakula@ 123456lumc.nl
                Author notes
                [* ]Correspondence: m.j.t.h.goumans@ 123456lumc.nl ; Tel.: +31-71-526-9277; Fax: +31-71-526-8270
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-9344-6746
                Article
                Publisher ID: ijms-19-02585
                DOI: 10.3390/ijms19092585
                PMC ID: 6164161
                PubMed ID: 30200294
                SO-VID: 34c5de6b-7481-44d0-b7f2-d11f2739e49c
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 27 July 2018
                Date accepted : 23 August 2018
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: pulmonary arterial hypertension,transforming growth factor β,bone morphogenetic protein,signaling,pathophysiology,treatment
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: pulmonary arterial hypertension, transforming growth factor β, bone morphogenetic protein, signaling, pathophysiology, treatment

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