BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production
Author(s)
Type
Journal Article
Date Issued
2012-01-27
Date Acceptance
2011-12-12
Citation
PLOS One, 2012, 7 (1)
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.
use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Sponsor
Medical Research Council (MRC)
Medical Research Council (MRC)
Grant Number
G0701361
G1000758
Subjects
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
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