BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production.
<h4>Background</h4>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 vasoconstri...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0030075&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849727535100723200 |
|---|---|
| author | John E S Park Dongmin Shao Paul D Upton Patricia Desouza Ian M Adcock Rachel J Davies Nicholas W Morrell Mark J D Griffiths Stephen J Wort |
| author_facet | John E S Park Dongmin Shao Paul D Upton Patricia Desouza Ian M Adcock Rachel J Davies Nicholas W Morrell Mark J D Griffiths Stephen J Wort |
| author_sort | John E S Park |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methodology/principal finding</h4>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.<h4>Conclusions/significance</h4>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. |
| format | Article |
| id | doaj-art-9b533a4f3fde4c4a9173254ed3a1aed8 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-9b533a4f3fde4c4a9173254ed3a1aed82025-08-20T03:09:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0171e3007510.1371/journal.pone.0030075BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production.John E S ParkDongmin ShaoPaul D UptonPatricia DesouzaIan M AdcockRachel J DaviesNicholas W MorrellMark J D GriffithsStephen J Wort<h4>Background</h4>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.<h4>Methodology/principal finding</h4>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.<h4>Conclusions/significance</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0030075&type=printable |
| spellingShingle | John E S Park Dongmin Shao Paul D Upton Patricia Desouza Ian M Adcock Rachel J Davies Nicholas W Morrell Mark J D Griffiths Stephen J Wort BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. PLoS ONE |
| title | BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. |
| title_full | BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. |
| title_fullStr | BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. |
| title_full_unstemmed | BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. |
| title_short | BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. |
| title_sort | bmp 9 induced endothelial cell tubule formation and inhibition of migration involves smad1 driven endothelin 1 production |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0030075&type=printable |
| work_keys_str_mv | AT johnespark bmp9inducedendothelialcelltubuleformationandinhibitionofmigrationinvolvessmad1drivenendothelin1production AT dongminshao bmp9inducedendothelialcelltubuleformationandinhibitionofmigrationinvolvessmad1drivenendothelin1production AT pauldupton bmp9inducedendothelialcelltubuleformationandinhibitionofmigrationinvolvessmad1drivenendothelin1production AT patriciadesouza bmp9inducedendothelialcelltubuleformationandinhibitionofmigrationinvolvessmad1drivenendothelin1production AT ianmadcock bmp9inducedendothelialcelltubuleformationandinhibitionofmigrationinvolvessmad1drivenendothelin1production AT racheljdavies bmp9inducedendothelialcelltubuleformationandinhibitionofmigrationinvolvessmad1drivenendothelin1production AT nicholaswmorrell bmp9inducedendothelialcelltubuleformationandinhibitionofmigrationinvolvessmad1drivenendothelin1production AT markjdgriffiths bmp9inducedendothelialcelltubuleformationandinhibitionofmigrationinvolvessmad1drivenendothelin1production AT stephenjwort bmp9inducedendothelialcelltubuleformationandinhibitionofmigrationinvolvessmad1drivenendothelin1production |