title: Bone Morphogenetic Protein 9 Enhances Lipopolysaccharide-Induced Leukocyte Recruitment to the Vascular Endothelium.
abstract: Bone morphogenetic protein (BMP)9 is a circulating growth factor that is part of the TGF-β superfamily and is an essential regulator of vascular endothelial homeostasis. Previous studies have suggested a role for BMP9 signaling in leukocyte recruitment to the endothelium, but the directionality of this effect and underlying mechanisms have not been elucidated. In this study, we report that BMP9 upregulates TLR4 expression in human endothelial cells and that BMP9 pretreatment synergistically increases human neutrophil recruitment to LPS-stimulated human endothelial monolayers in an in vitro flow adhesion assay. BMP9 alone did not induce neutrophil recruitment to the endothelium. We also show that E-selectin and VCAM-1, but not ICAM-1, are upregulated in response to BMP9 in LPS-stimulated human endothelial cells. Small interfering RNA knockdown of activin receptor-like kinase 1 inhibited the BMP9-induced expression of TLR4 and VCAM-1 and inhibited BMP9-induced human neutrophil recruitment to LPS-stimulated human endothelial cells. BMP9 treatment also increased leukocyte recruitment within the pulmonary circulation in a mouse acute endotoxemia model. These results demonstrate that although BMP9 alone does not influence leukocyte recruitment, it primes the vascular endothelium to mount a more intense response when challenged with LPS through an increase in TLR4, E-selectin, and VCAM-1 and ultimately through enhanced leukocyte recruitment.
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Appleby
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Claudia-Gabriela
authors.initials: CG
authors.lastname: Mitrofan
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Alexi
authors.initials: A
authors.lastname: Crosby
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Hoenderdos
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Katharine
authors.initials: K
authors.lastname: Lodge
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Upton
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Clara M
authors.initials: CM
authors.lastname: Yates
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Nash
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D008070:Lipopolysaccharides