Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2
Tatyana Novoyatleva, Nabham Rai, Baktybek Kojonazarov, Swathi Veeroju, Isabel Ben‐Batalla, Paola Caruso, Mazen Shihan, Nadine Presser, Elsa Götz, Carina Lepper, Sebastian Herpel, Grégoire Manaud, Frédéric Perros, Henning Gall, Hossein Ardeschir Ghofrani, Norbert Weißmann, Friedrich Grimminger, John Wharton, Martin R. Wilkins, Paul D. Upton, Sonja Loges, Nicholas W. Morrell, Werner Seeger, Ralph T. Schermuly
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.