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Loss of cAbl Tyrosine Kinase in Pulmonary Arterial Hypertension Causes Dysfunction of Vascular Endothelial Cells

Abstract : Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by the dysfunction of pulmonary endothelial cells (ECs) and obstructive vascular remodeling. The non-receptor tyrosine kinase c-Abelson (cAbl) plays central roles in regulating cell-cycle arrest, apoptosis, and senescence after cellular stress. We hypothesized that cAbl is down-activated in experimental and human PAH, thus leading to reduced DNA integrity and angiogenic capacity of pulmonary ECs from PAH patients (PAH-ECs). We found cAbl and phosphorylated cAbl levels to be lower in the endothelium of remodeled pulmonary vessels in the lungs of PAH patients than controls. Similar observations were obtained for the lungs of sugen+hypoxia (SuHx) and monocrotaline (MCT) rats with established pulmonary hypertension. These in situ abnormalities were also replicated in vitro, with cultured PAH-ECs displaying lower cAbl expression and activity and an altered DNA damage response and capacity of tube formation. Downregulation of cAbl by RNA-interference in Control-ECs or its inhibition with dasatinib resulted in genomic instability and the failure to form tubes, whereas upregulation of cAbl with DPH reduced DNA damage and apoptosis in PAH-ECs. Finally, we establish the existence of crosstalk between cAbl and bone morphogenetic protein receptor type II (BMPRII). This work identifies the loss of cAbl signaling as a novel contributor to pulmonary EC dysfunction associated with PAH.
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https://www.hal.inserm.fr/inserm-03678207
Contributor : Christophe Guignabert Connect in order to contact the contributor
Submitted on : Wednesday, May 25, 2022 - 11:26:30 AM
Last modification on : Wednesday, June 8, 2022 - 3:40:16 AM

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Benjamin Le Vely, Carole Phan, Nihel Berrebeh, Raphaël Thuillet, Mina Ottaviani, et al.. Loss of cAbl Tyrosine Kinase in Pulmonary Arterial Hypertension Causes Dysfunction of Vascular Endothelial Cells. American Journal of Respiratory Cell and Molecular Biology, American Thoracic Society, 2022, Online ahead of print. ⟨10.1165/rcmb.2021-0332oc⟩. ⟨inserm-03678207⟩

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