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.
Highlights
Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudomalignant phenotype
As Axl expression was strongly induced in pulmonary vessels (Supplementary Fig. 1g) and pulmonary arterial smooth muscle cells (PASMCs) in experimental pulmonary hypertension (PH) (Supplementary Fig. 1h), we explored the functional effect of Axl inhibition on human pulmonary arterial SMC (hPASMC) proliferation and migration using a clinically tested small molecule inhibitor R428 (BGB324)
We found an altered Axl expression in experimental PH and patients with IPAH and showed that Axl inhibition by R428 worsened experimental PH and augmented human pulmonary arterial ECs (hPAECs) apoptosis
Summary
Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudomalignant phenotype. Gas6-induced Axl signaling contributes to the survival of human pulmonary arterial ECs (hPAECs)[15], increases SMC proliferation and migration, blocks apoptosis[17,18], and regulates SMC immune heterogeneity and extracellular matrix remodeling[19]. Both proteins have been reported to be upregulated and activated in various human malignancies, in which their expression is tightly correlated with poor prognosis and increased invasiveness/ metastasis[20]. Our studies demonstrate the protective role of Gas6/Axl in PAH and highlight a novel liaison between Gas6/Axl and BMP/ BMPR2 signaling pathways
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