Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells

Robert Szulcek, Gonzalo Sanchez-Duffhues, Nina Rol, Xiaoke Pan, Roula Tsonaka, Chris Dickhoff, Lai Ming Yung, Xue D. Manz, Kondababu Kurakula, Szymon M. Kiełbasa, Hailiang Mei, Wim Timens, Paul B. Yu, Harm Jan Bogaard, Marie José Goumans

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)699-714
Number of pages16
JournalANGIOGENESIS
Volume23
Issue number4
Early online date2020
DOIs
Publication statusPublished - 1 Nov 2020

Keywords

  • Bone morphogenetic protein
  • Endothelial-to-mesenchymal transition
  • Interleukin-6
  • Pulmonary endothelial cells
  • Pulmonary hypertension

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