Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells.

Paul D Upton,Nicholas W Morrell,Patricia M De Souza,Mark J D Griffiths,Rachel J Davies,John E S Park,Stephen J Wort

doi:10.1242/jcs.239715

Paul D Upton, Nicholas W Morrell + Show 5 more

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https://doi.org/10.1242/jcs.239715

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Abstract

ABSTRACTBone morphogenetic protein 9 (BMP9) and BMP10 are circulating ligands that mediate endothelial cell (EC) protection via complexes of the type I receptor ALK1 and the type II receptors activin type-IIA receptor (ACTR-IIA) and bone morphogenetic type II receptor (BMPR-II). We previously demonstrated that BMP9 induces the expression of interleukin-6, interleukin-8 and E-selectin in ECs and might influence their interactions with monocytes and neutrophils. We asked whether BMP9 and BMP10 regulate the expression of chemokine (C-C motif) ligand 2 (CCL2), a key chemokine involved in monocyte–macrophage chemoattraction. Here, we show that BMP9 and BMP10 repress basal CCL2 expression and release from human pulmonary artery ECs and aortic ECs. The repression was dependent on ALK1 and co-dependent on ACTR-IIA and BMPR-II. Assessment of canonical Smad signalling indicated a reliance of this response on Smad4. Of note, Smad1/5 signalling contributed only at BMP9 concentrations similar to those in the circulation. In the context of inflammation, BMP9 did not alter the induction of CCL2 by TNF-α. As CCL2 promotes monocyte/macrophage chemotaxis and endothelial permeability, these data support the concept that BMP9 preserves basal endothelial integrity.

Highlights

Bone morphogenetic protein 9 (BMP9) and BMP10 are circulating members of the transforming growth factor-β (TGF-β) superfamily of ligands that directly activate signalling and mediate functional responses in endothelial cells
BMP9 and BMP10 inhibit CCL2 production by human pulmonary artery endothelial cells (HPAECs) To establish whether BMP9 altered the expression of CCL2 in HPAECs, cells were treated with control medium alone or supplemented with 1 ng/ml BMP9 for 2, 4, 8 and 12 h
Inhibition of CCL2 is dependent on ALK1 and co-dependent on ACTR-IIA and BMPR-II ALK1 and BMPR-II form a BMP9-responsive receptor complex on endothelial cells, so we addressed how loss of ALK1 and BMPR-II, induced through siRNA transfection, might impact on the ability of BMP9 to inhibit CCL2 production by HPAECs

Summary

Introduction

Bone morphogenetic protein 9 (BMP9) and BMP10 are circulating members of the transforming growth factor-β (TGF-β) superfamily of ligands that directly activate signalling and mediate functional responses in endothelial cells. BMP9 and BMP10 activate endothelial cell signalling via binding to heteromeric complexes of type I and type II receptors These ligands bind with high affinity to the type I receptor, ALK1 (EC50=50 pg/ml), which is expressed at high levels by endothelial cells (Scharpfenecker et al, 2007; David et al, 2007; Upton et al, 2009; Mahmoud et al, 2009). BMP10 has broader type II receptor selectivity, binding to the activin type IIB receptor (ACTR-IIB), this receptor is not expressed at appreciable levels by endothelial cells (Townson et al, 2012)

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