2. Academic Validation
  3. Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2

Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2

  • Commun Biol. 2021 Aug 24;4(1):1002. doi: 10.1038/s42003-021-02531-1.
Tatyana Novoyatleva 1,  Nabham Rai 2,  Baktybek Kojonazarov 2 3,  Swathi Veeroju 2,  Isabel Ben-Batalla 4 5,  Paola Caruso 6,  Mazen Shihan 2,  Nadine Presser 2,  Elsa Götz 2,  Carina Lepper 2,  Sebastian Herpel 2,  Grégoire Manaud 7,  Frédéric Perros 7,  Henning Gall 2,  Hossein Ardeschir Ghofrani 2,  Norbert Weissmann 2,  Friedrich Grimminger 2,  John Wharton 8,  Martin Wilkins 8,  Paul D Upton 6,  Sonja Loges 4 5,  Nicholas W Morrell 6,  Werner Seeger 2 9,  Ralph T Schermuly 10
Affiliations

Affiliations

  • 1 Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany. [email protected].
  • 2 Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany.
  • 3 Institute for Lung Health, Giessen, Germany.
  • 4 Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 5 Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 6 Department of Medicine, University of Cambridge, Cambridge, UK.
  • 7 Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Le Kremlin Bicêtre, France.
  • 8 Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College London, London, UK.
  • 9 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 10 Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany. [email protected].
PMID: 34429509 DOI: 10.1038/s42003-021-02531-1
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.

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