Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice

Abstract

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives: To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice ( N = 12) resulted in increased lung vascular permeability ( P = 0.022), interstitial edema ( P = 0.0047), and neutrophil extravasation ( P = 0.029) compared with IgG control treatment ( N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice ( N = 8) prevented inhaled LPS–induced lung injury ( P = 0.0027) and edema ( P < 0.0001). In endotoxemic mice ( N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis ( N = 10), circulating concentratons of BMP9 were also markedly reduced ( P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.

BMP9 and BMP10: Two close vascular quiescence partners that stand out

“…142 Circulating BMP9 has also been measured in a small cohort (n = 10) of patients with systemic inflammatory response syndrome (SIRS) and sepsis, and was found to be significantly reduced compared to healthy controls. 31…”

“…To our knowledge, no one has studied the regulation of BMP9 expression in HSCs. What has been shown in pathological conditions, is that acute liver injury caused by partial hepatectomy or by the injection of carbon tetrachloride (CCL4) or lipopolysaccharide (LPS) results in transient down‐regulation of Bmp9 mRNA 17,31 . Liver Bmp9 mRNA and protein levels are also decreased in high‐fat diet mice and obese db/db mice 32 .…”

The Dual Effect of the BMP9–ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement?

“…The main effector pathway of BMP9 signaling is Smad1/5/8, although it can vary depending on the cell type and cellular context. BMP9 transduces signals through Smad1/5/8, as it has been described in numerous studies on endothelial cells [79,[96][97][98][99][100][101][102]. In the hepatocellular carcinoma cell line HepG2, BMP9 induces phospho-Smad1/5/8 phosphorylation leading to increased survival [103].…”

SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

“…BMP9 and BMP10 are ligands that mediate endothelial cell protection and repress CCL2 expression, a chemokine involved in monocyte-macrophage recruitment. [16][17][18][19] The observed increase in BMP10 in the SU5416H21/28 group suggests a possible counter-regulatory response to perturbation of the BMPR2 axis. These findings suggest important effects of SU5416/hypoxia on the BMPR2 axis that change over time as the model develops.…”