Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-alpha-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2
Author(s)
Type
Journal Article
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 whereas BMP9/BMP10 alone had no effect on monocyte recruitment, at higher concentrations both cytokines synergized 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 up-regulated expression levels of E-selectin, vascular cell adhesion molecule (VCAM-1), and intercellular adhesion molecule 1 (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 up-regulation 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 up-regulation 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 IκBα protein expression, but did not alter p65/RelA levels. Our findings suggest that higher concentrations of BMP9/BMP10 synergize with TNFα to induce the up-regulation 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.
Date Issued
2017-08-18
Online Publication Date
2017-08-18
2018-11-22T11:20:33Z
Date Acceptance
2017-06-01
ISSN
0021-9258
Publisher
American Society for Biochemistry and Molecular Biology
Start Page
13714
End Page
13726
Journal / Book Title
Journal of Biological Chemistry
Volume
292
Issue
33
Copyright Statement
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. This is an open access article distributed under the terms of a Creative Commons Attribution 4.0 International licence (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000407942400019&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
HEREDITARY HEMORRHAGIC TELANGIECTASIA
PULMONARY ARTERIAL-HYPERTENSION
TNF-ALPHA
LEUKOCYTE RECRUITMENT
CANCER PROGRESSION
SMAD PROTEINS
KAPPA-B
CELLS
EXPRESSION
ATHEROSCLEROSIS
SMAD transcription factor
atherosclerosis
bone morphogenetic protein (BMP)
endothelial cell
monocyte
Activin Receptors, Type I
Activin Receptors, Type II
Aorta
Bone Morphogenetic Proteins
Cell Adhesion
Cells, Cultured
E-Selectin
Endothelium, Vascular
Growth Differentiation Factors
Humans
Intercellular Adhesion Molecule-1
Kinetics
Monocytes
Phosphorylation
Protein Kinase Inhibitors
Protein Processing, Post-Translational
Pyrazoles
Pyrimidines
RNA Interference
Signal Transduction
Tumor Necrosis Factor-alpha
Up-Regulation
Vascular Cell Adhesion Molecule-1
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Publication Status
Published
Date Publish Online
2017-06-23