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


RESULTS
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
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.
Unit of Critical Care, Royal Brompton Hospital, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
John E S
JE
Park
Dongmin
D
Shao
Paul D
PD
Upton
Patricia
P
Desouza
Ian M
IM
Adcock
Rachel J
RJ
Davies
Nicholas W
NW
Morrell
Mark J D
MJ
Griffiths
Stephen J
SJ
Wort
D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D055427:Growth Differentiation Factor 2 / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D055427:Growth Differentiation Factor 2; D009842:Oligopeptides; D010880:Piperidines; D051898:Smad1 Protein; C086539:BQ 788