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Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2

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Seeger,  Werner
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Novoyatleva, T., Rai, N., Kojonazarov, B., Veeroju, S., Ben-Batalla, I., Caruso, P., et al. (2021). Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2. COMMUNICATIONS BIOLOGY, 4(1): 1002. doi:10.1038/s42003-021-02531-1.


Cite as: http://hdl.handle.net/21.11116/0000-0009-1B53-C
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. Novoyatleva et al investigate the role of receptor tyrosine kinase Axl in Pulmonary arterial hypertension (PAH), finding that the small molecule inhibitor R428 reduces human pulmonary arterial smooth muscle cells proliferation and migration, but causes toxicity in human pulmonary arterial endothelial cells. They further show that Axl enhances endothelial BMPR2 signaling, altogether providing insights into mechanisms of PAH.