PloS one, 2012-01, Vol.7 (1), p.e30075
2012
Details
- Autor(en) / Beteiligte
- Titel
- BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production
- Ist Teil von
- PloS one, 2012-01, Vol.7 (1), p.e30075
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0030075Titel-ID: cdi_plos_journals_1323434502
- Format
- –
- Schlagworte
- Angiogenesis, Biology, Bone morphogenetic protein 2, Bone morphogenetic proteins, Cell adhesion & migration, Cell migration, Cell Movement - drug effects, Cell Movement - genetics, Cell Proliferation - drug effects, Cells, Cultured, Chlamydia, Chlamydia pneumoniae, Clinical medicine, Critical care, Crosstalk, Down-Regulation - drug effects, Endothelial cells, Endothelial Cells - drug effects, Endothelial Cells - metabolism, Endothelial Cells - physiology, Endothelin, Endothelin 1, Endothelin B Receptor Antagonists, Endothelin-1 - antagonists & inhibitors, Endothelin-1 - biosynthesis, Endothelin-1 - genetics, Endothelin-1 - metabolism, Endothelium, Enzyme-linked immunosorbent assay, Gene expression, Growth Differentiation Factor 2 - pharmacology, Growth Differentiation Factor 2 - physiology, Heart, Humans, Hypertension, Inhibition, Kinases, Leukocyte migration, MAP kinase, Medicine, Mitogens, Mortality, Mutation, Neovascularization, Physiologic - drug effects, Neovascularization, Physiologic - genetics, Oligopeptides - pharmacology, Pathogenesis, Physiological aspects, Piperidines - pharmacology, Polymerase chain reaction, Proteins, Pulmonary arteries, Pulmonary artery, Pulmonary Artery - cytology, Pulmonary Artery - drug effects, Pulmonary Artery - metabolism, Pulmonary Artery - physiology, Pulmonary fibrosis, Pulmonary hypertension, Receptors, Ribonucleic acid, RNA, RNA-mediated interference, Rodents, Signal transduction, Signaling, Smad1 Protein - genetics, Smad1 Protein - metabolism, Smad1 Protein - physiology, Smad4 protein, Transcription, Tumor necrosis factor-TNF