Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endotheli
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ORIGINAL PAPER
Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells Robert Szulcek1,2 · Gonzalo Sanchez‑Duffhues1 · Nina Rol2 · Xiaoke Pan2 · Roula Tsonaka3 · Chris Dickhoff4 · Lai Ming Yung5 · Xue D. Manz2 · Kondababu Kurakula1 · Szymon M. Kiełbasa6 · Hailiang Mei6 · Wim Timens7 · Paul B. Yu5 · Harm‑Jan Bogaard2 · Marie‑José Goumans1 Received: 20 May 2020 / Accepted: 1 August 2020 © The Author(s) 2020
Abstract Imbalanced transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling are postulated to favor a pathological pulmonary endothelial cell (EC) phenotype in pulmonary arterial hypertension (PAH). BMP9 is shown to reinstate BMP receptor type-II (BMPR2) levels and thereby mitigate hemodynamic and vascular abnormalities in several animal models of pulmonary hypertension (PH). Yet, responses of the pulmonary endothelium of PAH patients to BMP9 are unknown. Therefore, we treated primary PAH patient-derived and healthy pulmonary ECs with BMP9 and observed that stimulation induces transient transcriptional signaling associated with the process of endothelial-to-mesenchymal transition (EndMT). However, solely PAH pulmonary ECs showed signs of a mesenchymal trans-differentiation characterized by a loss of VE-cadherin, induction of transgelin (SM22α), and reorganization of the cytoskeleton. In the PAH cells, a prolonged EndMT signaling was found accompanied by sustained elevation of pro-inflammatory, pro-hypoxic, and pro-apoptotic signaling. Herein we identified interleukin-6 (IL6)-dependent signaling to be the central mediator required for the BMP9-induced phenotypic change in PAH pulmonary ECs. Furthermore, we were able to target the BMP9-induced EndMT process by an IL6 capturing antibody that normalized autocrine IL6 levels, prevented mesenchymal transformation, and maintained a functional EC phenotype in PAH pulmonary ECs. In conclusion, our results show that the BMP9-induced aberrant EndMT in PAH pulmonary ECs is dependent on exacerbated pro-inflammatory signaling mediated through IL6. Keywords Pulmonary hypertension · Pulmonary endothelial cells · Endothelial-to-mesenchymal transition · Bone morphogenetic protein · Interleukin-6
Introduction Progressive occlusive remodeling of the distal pulmonary vasculature is the hallmark of pulmonary arterial hypertension (PAH), a heterogenous group of deadly lung disorders * Marie‑José Goumans [email protected] 1
Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
2
Department of Pulmonary Diseases, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam Cardiovascular Sciences (ACS), Amsterdam, The Netherlands
3
Department of Biomedical Data Sciences, Medical Statistics Section, LUMC, Leiden, The Netherlands
clinically defined by a highly increased mean pulmonary artery pressure at rest in the absence of other causes of precapillary pulmonary hypertension (PH) [1, 2]. Histologically, PAH i
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