Role of Endothelial G Protein-Coupled Receptor Kinase 2 in Angioedema
Jessica Gambardella, Daniela Sorriento, Maria Bova, Mariarosaria Rusciano, Stefania Loffredo, Xujun Wang, Angelica Petraroli, Laura R. Carucci, Ilaria Mormile, Marco Oliveti, Marco Bruno Morelli, Antonella Fiordelisi, Giuseppe Spadaro, Pietro Campiglia, Marina Sala, Bruno Trimarco, Guido Iaccarino, Gaetano Santulli, Michele Ciccarelli
Abstract
Excessive BK (bradykinin) stimulation is responsible for the exaggerated permeabilization of the endothelium in angioedema. However, the molecular mechanisms underlying these responses have not been investigated. BK receptors are Gq-protein-coupled receptors phosphorylated by GRK2 (G protein-coupled receptor kinase 2) with a hitherto unknown biological and pathophysiological significance. In the present study, we sought to identify the functional role of GRK2 in angioedema through the regulation of BK signaling. We found that the accumulation of cytosolic Ca 2+ in endothelial cells induced by BK was sensitive to GRK2 activity, as it was significantly augmented by inhibiting the kinase. Accordingly, permeabilization and NO production induced by BK were enhanced, as well. In vivo, mice with reduced GRK2 levels in the endothelium (Tie2-CRE/GRK2 fl+/fl − ) exhibited an increased response to BK in terms of vascular permeability and extravasation. Finally, patients with reduced GRK2 levels displayed a severe phenotype of angioedema. Taken together, these findings establish GRK2 as a novel pivotal regulator of BK signaling with an essential role in the pathophysiology of vascular permeability and angioedema.