Bone morphogenetic protein (BMP) 9 and BMP10 enhance tumor necrosis factor-α-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2

Claudia-Gabriela Mitrofan, Sarah L Appleby, Gerard B Nash, Ziad Mallat, Edwin R Chilvers, Paul D Upton, Nicholas W Morrell

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20 Citations (Scopus)
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Abstract

Bone morphogenetic proteins 9 and 10 (BMP9/BMP10) are circulating cytokines with important roles in endothelial homeostasis. The aim of this study was to investigate the roles of BMP9 and BMP10 in mediating monocyte-endothelial interactions using an in vitro flow adhesion assay. Herein, we report that while BMP9/BMP10 alone had no effect on monocyte recruitment, at higher concentrations both cytokines synergised with Tumor necrosis factor-α (TNFα) to increase recruitment to the vascular endothelium. The BMP9/BMP10-mediated increase in monocyte recruitment in the presence of TNFα was associated with upregulated expression levels of E-selectin, VCAM-1 and ICAM-1 on endothelial cells. Using siRNAs to type I and II BMP receptors and the signaling intermediaries (Smads), we demonstrated a key role for ALK2 in the BMP9/BMP10-induced surface expression of E-selectin, and both ALK1 and ALK2 in the upregulation of VCAM-1 and ICAM-1. The type II receptors, BMPR-II and ACTR-IIA were both required for this response, as was Smad1/5. The upregulation of cell surface adhesion molecules by BMP9/10 in the presence of TNFα was inhibited by LDN193189, which inhibits ALK2 but not ALK1. Furthermore, LDN193189 inhibited monocyte recruitment induced by TNFα and BMP9/10. BMP9/10 increased basal IκB-α protein expression, but did not alter p65/RelA levels. Our findings suggest that higher concentrations of BMP9/BMP10 synergise with TNFα to induce the upregulation of endothelial selectins and adhesion molecules, ultimately resulting in increased monocyte recruitment to the vascular endothelium. This process is mediated mainly via the ALK2 type I receptor, BMPR-II/ACTR-IIA type II receptors, and downstream Smad1/5 signaling.

Original languageEnglish
JournalJournal of Biological Chemistry
Early online date23 Jun 2017
DOIs
Publication statusE-pub ahead of print - 23 Jun 2017

Keywords

  • atherosclerosis
  • bone morphogenetic protein (BMP)
  • endothelial cell
  • monocyte
  • SMAD transcription factor

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