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
  • 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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