TY - JOUR
T1 - Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells
AU - Szulcek, Robert
AU - Sanchez-Duffhues, Gonzalo
AU - Rol, Nina
AU - Pan, Xiaoke
AU - Tsonaka, Roula
AU - Dickhoff, Chris
AU - Yung, Lai Ming
AU - Manz, Xue D.
AU - Kurakula, Kondababu
AU - Kiełbasa, Szymon M.
AU - Mei, Hailiang
AU - Timens, Wim
AU - Yu, Paul B.
AU - Bogaard, Harm Jan
AU - Goumans, Marie José
N1 - Funding Information: This work was supported by the Dutch CardioVascular Alliance (DCVA) [2012-08, 2014-11] awarded to the Phaedra and the RECONNECT consortium as well as the Impulse Grant 2018 awarded to the Phaedra IMPACT consortium. These Grants include collective funding by the Dutch Heart Foundation, Dutch Federation of University Medical Centers, The Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences. GSD is supported by a Trampoline Grant from AFM-Telethon [22379] and FOP Italia. XDM is funded by a research Grant of the Institute for CardioVascular Research (ICaR-VU) at VU University Medical Center, Amsterdam, the Netherlands. Publisher Copyright: © 2020, The Author(s).
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - Bone morphogenetic protein
KW - Endothelial-to-mesenchymal transition
KW - Interleukin-6
KW - Pulmonary endothelial cells
KW - Pulmonary hypertension
UR - http://www.scopus.com/inward/record.url?scp=85089476401&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85089476401&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/32813135
U2 - https://doi.org/10.1007/s10456-020-09741-x
DO - https://doi.org/10.1007/s10456-020-09741-x
M3 - Article
C2 - 32813135
SN - 0969-6970
VL - 23
SP - 699
EP - 714
JO - ANGIOGENESIS
JF - ANGIOGENESIS
IS - 4
ER -