Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-α-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2

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.

Selective BMP-9 Inhibition Partially Protects Against Experimental Pulmonary Hypertension

“…Consistent with our present findings, BMP9 treatment has been found to improve aberrant alveolar development and reduced lung inflammation and fibrosis but did not improve aberrant vascularization (arterial medial wall thickness and muscularization) and right ventricular hypertrophy 37 . In line with this notion, BMP9 and BMP10 can synergize with TNFα to induce the upregulation of endothelial selectins and adhesion molecules and the secretion of various key pro-inflammatory mediators 38,39 , and are therefore likely to contribute to the proinflammatory signature of the dysfunctional endothelium in PAH 40 .…”

A Signaling Crosstalk between BMP9 and HGF/c-Met Regulates Mouse Adult Liver Progenitor Cell Survival

“…ALK1 and ALK2 type I receptors might indeed have different signaling properties. Supporting this, complementary actions of ALK1 and ALK2 mediate the BMP9/BMP10 effects in human aortic endothelial cells, enhancing TNF-α-induced monocyte recruitment to vascular endothelium [36]. Interestingly, a BMP6 mutant specifically defective in ALK2 binding but with normal affinity for ALK3 and ALK6 was not able to induce alkaline phosphatase expression, a target of p38MAPK [37], highlighting a key role for ALK2 on p38MAPK activation.…”

Soluble endoglin regulates expression of angiogenesis-related proteins and induction of arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia

“…Accordingly, it has been shown that sEng can modulate integrin-mediated cell adhesion involving membrane-bound endothelial endoglin ( Rossi et al, 2013 , 2016 ; Ruiz-Remolina et al, 2017 ), and this function might have an impact on the active angiogenesis and vascular remodeling processes in the neovascularized retina of Eng -iKO e mice. In this regard, upon an inflammatory stimulus, leukocyte recruitment to the vasculature involves endothelial endoglin, via leukocyte integrins ( Rossi et al, 2013 ), as well as BMP9 ( Mitrofan et al, 2017 ). Because the inflammatory infiltrate of leukocytes appears to be involved in the vascular remodeling leading to AVMs in HHT patients ( van Laake et al, 2006 ; Zhang et al, 2016 ), a role for sEng in this cell adhesion-dependent process can be postulated ( Dingenouts et al, 2015 ; Rossi et al, 2015 ).…”