The interaction between Axl receptor tyrosine kinase and its ligand Growth arrest-specific 6 (Gas6) plays a role in proliferation, migration, differentiation, adhesion, resistance to apoptosis and survival through a complex network of intracellular second messengers and has been implicated in the progression of a wide number of malignancies. Axl overexpression has emerged as a key molecular determinant underlying the development of acquired resistance to targeted anticancer agents. While many studies have focused on studying Gas6 and Axl in inflammation and cancer, the role of Gas6/Axl axis in Pulmonary Arterial Hypertension (PAH) is unknown.
An upregulated expression of Axl and Gas6 in pulmonary arteries (PAs) and Pulmonary Arterial Smooth Muscle Cells (PASMCs) of experimental Su/Hox and MCT rat models and clinical pulmonary hypertension (PH) (patients with idiopathic pulmonary arterial hypertension, IPAH) have been determined. Inhibition of Axl receptor by the clinically applicable small molecular inhibitor R428 (BGB324) diminished the proliferation and migration of hPASMCs. In vivo, R428 surprisingly aggravated experimental PH in rats as shown by an increase in right ventricular systolic pressure (RVSP) and RV hypertrophy, deterioration of pulmonary vascular remodeling and a decrease in cardiac output. R428 elevated pro-proliferative and inflammatory responses, exacerbated oxidative stress, augmented EC apoptosis and abrogated BMPRII signaling pathway. In vitro, R428 induced hPAECs apoptosis in a dose-dependent manner and increased expression and release of adhesion molecules, markers of endothelial dysfunction. BMP9 and Gas6 stimulation of vascular cells induced Axl phosphorylation and inversed R428-induced cell death. R428 inhibited BMP/SMAD1-5-8/ID1 signaling pathway, by virtue of BMPRII protein deterioration. Importantly, both Axl and BMPRII co-interact in ECs, suggesting a previously unrecognized association between these two receptors.
Taken together, our studies are the first to demonstrate the protective role of Gas6/Axl axis in PH and highlight a novel liaison between Gas6/Axl and BMP/BMPRII signaling pathways.
This abstract was funded by SFB 1213 (Projects: B04, CP02, and A9).