TY - JOUR
T1 - Role of endothelial G protein-coupled receptor kinase 2 in angioedema
AU - Gambardella, Jessica
AU - Sorriento, Daniela
AU - Bova, Maria
AU - Rusciano, Mariarosaria
AU - Loffredo, Stefania
AU - Wang, Xujun
AU - Petraroli, Angelica
AU - Carucci, Laura
AU - Mormile, Ilaria
AU - Oliveti, Marco
AU - Morelli, Marco Bruno
AU - Fiordelisi, Antonella
AU - Spadaro, Giuseppe
AU - Campiglia, Pietro
AU - Sala, Marina
AU - Trimarco, Bruno
AU - Iaccarino, Guido
AU - Santulli, Gaetano
AU - Ciccarelli, Michele
N1 - Funding Information:
The study was supported by FARB-2018 Salerno (to M. Ciccarelli), by the American Heart Association (POST35211151 to J. Gambardella), and by the National Institutes of Health (NIH: R01-DK123259, R01-HL146691, T32-HL144456,R00-DK107895, R56-AG066431, P30-DK020541, and R01-DK033823 to G. Santulli).
Publisher Copyright:
© 2020 American Heart Association, Inc.
PY - 2020
Y1 - 2020
N2 - 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 Ca2+ 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/GRK2fl+/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.
AB - 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 Ca2+ 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/GRK2fl+/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.
KW - Angioedema
KW - Atherosclerosis
KW - Bradykinin
KW - Endothelium
KW - Phenotype
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U2 - 10.1161/HYPERTENSIONAHA.120.15130
DO - 10.1161/HYPERTENSIONAHA.120.15130
M3 - Article
C2 - 32895019
AN - SCOPUS:85092750063
SN - 0194-911X
VL - 76
SP - 1625
EP - 1636
JO - Hypertension
JF - Hypertension
IS - 5
ER -