BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production

Title: BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production
Authors: Park, JE
Shao, D
Upton, PD
Desouza, P
Adcock, IM
Davies, RJ
Morrell, NW
Griffiths, MJ
Wort, SJ
Item Type: Journal Article
Issue Date: 27-Jan-2012
Date of Acceptance: 12-Dec-2011
URI: http://hdl.handle.net/10044/1/31755
DOI: http://dx.doi.org/10.1371/journal.pone.0030075
ISSN: 1932-6203
Publisher: Public Library of Science
Journal / Book Title: PLOS One
Volume: 7
Issue: 1
Copyright Statement: © 2012 Park et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: G0701361
G1000758
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MULTIDISCIPLINARY SCIENCES
PULMONARY ARTERIAL-HYPERTENSION
MORPHOGENETIC PROTEIN-RECEPTOR
GERMLINE MUTATIONS
KINASE INHIBITORS
SIGNALING PATHWAY
BMPR2 MUTATION
EXPRESSION
ACTIVATION
PROLIFERATION
BINDING
Cell Movement
Cell Proliferation
Cells, Cultured
Down-Regulation
Endothelial Cells
Endothelin B Receptor Antagonists
Endothelin-1
Growth Differentiation Factor 2
Humans
Neovascularization, Physiologic
Oligopeptides
Piperidines
Pulmonary Artery
Smad1 Protein
Cell Movement/*drug effects/genetics Cell Proliferation/drug effects Cells, Cultured Down-Regulation/drug effects Endothelial Cells/*drug effects/metabolism/physiology Endothelin-1/antagonists & inhibitors/*biosynthesis/genetics/metabolism Growth Differentiation Factor 2/*pharmacology/physiology Humans Neovascularization, Physiologic/*drug effects/genetics Oligopeptides/pharmacology Piperidines/pharmacology Pulmonary Artery/cytology/drug effects/metabolism/physiology Receptor, Endothelin B/antagonists & inhibitors Smad1 Protein/genetics/metabolism/*physiology
General Science & Technology
MD Multidisciplinary
Notes: Park, John E S Shao, Dongmin Upton, Paul D Desouza, Patricia Adcock, Ian M Davies, Rachel J Morrell, Nicholas W Griffiths, Mark J D Wort, Stephen J G0701361/Medical Research Council/United Kingdom PG/07/032/22768/British Heart Foundation/United Kingdom RG/08/002/24718/British Heart Foundation/United Kingdom PLoS One. 2012;7(1):e30075. Epub 2012 Jan 27. BACKGROUND: Bone morphogenetic proteins (BMPs) and their receptors, such as bone morphogenetic protein receptor (BMPR) II, have been implicated in a wide variety of disorders including pulmonary arterial hypertension (PAH). Similarly, endothelin-1 (ET-1), a mitogen and vasoconstrictor, is upregulated in PAH and endothelin receptor antagonists are used in its treatment. We sought to determine whether there is crosstalk between BMP signalling and the ET-1 axis in human pulmonary artery endothelial cells (HPAECs), possible mechanisms involved in such crosstalk and functional consequences thereof. METHODOLOGY/PRINCIPAL FINDING: Using western blot, real time RT-PCR, ELISA and small RNA interference methods we provide evidence that in HPAECs BMP-9, but not BMP-2, -4 and -6 significantly stimulated ET-1 release under physiological concentrations. This release is mediated by both Smad1 and p38 MAPK and is independent of the canonical Smad4 pathway. Moreover, knocking down the ALK1 receptor or BMPR II attenuates BMP-9 stimulated ET-1 release, whilst causing a significant increase in prepro ET-1 mRNA transcription and mature peptide release. Finally, BMP-9 induced ET-1 release is involved in both inhibition of endothelial cell migration and promotion of tubule formation. CONCLUSIONS/SIGNIFICANCE: Although our data does not support an important role for BMP-9 as a source of increased endothelial ET-1 production seen in human PAH, BMP-9 stimulated ET-1 production is likely to be important in angiogenesis and vascular stability. However, increased ET-1 production by endothelial cells as a consequence of BMPR II dysfunction may be clinically relevant in the pathogenesis of PAH.
Publication Status: Published
Article Number: e30075
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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