BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production
| Autor: | Paul D. Upton, Mark J.D. Griffiths, Stephen J. Wort, Nicholas W. Morrell, Rachel J. Davies, John E. S. Park, Dongmin Shao, Patricia deSouza, Ian M. Adcock |
|---|---|
| Přispěvatelé: | Upton, Paul [0000-0003-2716-4921], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, Medical Research Council (MRC) |
| Rok vydání: | 2012 |
| Předmět: |
Non-Clinical Medicine
Angiogenesis lcsh:Medicine 030204 cardiovascular system & hematology Cardiovascular Biochemistry ACTIVATION 0302 clinical medicine Piperidines Cell Movement BINDING Molecular Cell Biology Growth Differentiation Factor 2 Signaling in Cellular Processes Bone morphogenetic protein receptor lcsh:Science Receptor Cells Cultured 0303 health sciences Multidisciplinary Endothelin-1 Mechanisms of Signal Transduction PROLIFERATION GERMLINE MUTATIONS Signaling Cascades Cell biology Endothelin B Receptor Antagonists Endothelial stem cell MORPHOGENETIC PROTEIN-RECEPTOR Science & Technology - Other Topics Medicine 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 SIGNALING PATHWAY Cellular Types Oligopeptides BMPR2 MUTATION Research Article Signal Transduction EXPRESSION PULMONARY ARTERIAL-HYPERTENSION medicine.medical_specialty General Science & Technology GDF2 Down-Regulation Neovascularization Physiologic Biology Pulmonary Artery Bone morphogenetic protein Smad1 Protein 03 medical and health sciences Internal medicine MD Multidisciplinary medicine Humans 030304 developmental biology Cell Proliferation Science & Technology MULTIDISCIPLINARY SCIENCES lcsh:R KINASE INHIBITORS Endothelial Cells Endothelin 1 Endocrinology lcsh:Q |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 1, p e30075 (2012) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|