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Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2

Published version
Peer-reviewed

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Authors

Novoyatleva, Tatyana  ORCID logo  https://orcid.org/0000-0002-3367-9940
Rai, Nabham 
Kojonazarov, Baktybek 
Veeroju, Swathi 
Ben-Batalla, Isabel 

Abstract

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.

Description

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

Journal Title

Communications Biology

Conference Name

Journal ISSN

2399-3642

Volume Title

4

Publisher

Nature Publishing Group UK
Sponsorship
Deutsche Forschungsgemeinschaft (German Research Foundation) (268555672, 268555672)