Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2.
Authors
Rai, Nabham
Kojonazarov, Baktybek
Veeroju, Swathi
Ben-Batalla, Isabel
Shihan, Mazen
Presser, Nadine
Götz, Elsa
Lepper, Carina
Herpel, Sebastian
Manaud, Grégoire
Weissmann, Norbert
Loges, Sonja
Publication Date
2021-08-24Journal Title
Commun Biol
ISSN
2399-3642
Publisher
Springer Science and Business Media LLC
Volume
4
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Novoyatleva, T., Rai, N., Kojonazarov, B., Veeroju, S., Ben-Batalla, I., Caruso, P., Shihan, M., et al. (2021). Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2.. Commun Biol, 4 (1) https://doi.org/10.1038/s42003-021-02531-1
Abstract
Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudo-malignant phenotype. We investigated the expression and the role of the receptor tyrosine kinase Axl in experimental (i.e., monocrotaline and Su5416/hypoxia treated rats) and clinical PAH. In vitro Axl inhibition by R428 and Axl knock-down inhibited growth factor-driven proliferation and migration of non-PAH and PAH PASMCs. Conversely, Axl overexpression conferred a growth advantage. Axl declined in PAECs of PAH patients. Axl blockage inhibited BMP9 signaling and increased PAEC apoptosis, while BMP9 induced Axl phosphorylation. Gas6 induced SMAD1/5/8 phosphorylation and ID1/ID2 increase were blunted by BMP signaling obstruction. Axl association with BMPR2 was facilitated by Gas6/BMP9 stimulation and diminished by R428. In vivo R428 aggravated right ventricular hypertrophy and dysfunction, abrogated BMPR2 signaling, elevated pulmonary endothelial cell apoptosis and loss. Together, Axl is a key regulator of endothelial BMPR2 signaling and potential determinant of PAH.
Keywords
Article, /631/80/86/2368, /631/80/82/23, /631/443/592/1540, /38/77, /38/109, /14/63, /13/2, /96/95, /13/51, article
Sponsorship
Deutsche Forschungsgemeinschaft (German Research Foundation) (268555672, 268555672)
Identifiers
s42003-021-02531-1, 2531
External DOI: https://doi.org/10.1038/s42003-021-02531-1
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333222
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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