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.

Role of endothelial g protein-coupled receptor kinase 2 in angioedema / Gambardella, J.; Sorriento, D.; Bova, M.; Rusciano, M.; Loffredo, S.; Wang, X.; Petraroli, A.; Carucci, L.; Mormile, I.; Oliveti, M.; Bruno Morelli, M.; Fiordelisi, A.; Spadaro, G.; Campiglia, P.; Sala, M.; Trimarco, B.; Iaccarino, G.; Santulli, G.; Ciccarelli, M.. - In: HYPERTENSION. - ISSN 0194-911X. - 76:5(2020), pp. 1625-1636. [10.1161/HYPERTENSIONAHA.120.15130]

Role of endothelial g protein-coupled receptor kinase 2 in angioedema

Gambardella J.;Sorriento D.;Bova M.;Rusciano M.;Loffredo S.;Carucci L.;Mormile I.;Oliveti M.;Fiordelisi A.;Spadaro G.;Sala M.;Trimarco B.;Iaccarino G.;Santulli G.;Ciccarelli M.
2020

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 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.
2020
Role of endothelial g protein-coupled receptor kinase 2 in angioedema / Gambardella, J.; Sorriento, D.; Bova, M.; Rusciano, M.; Loffredo, S.; Wang, X.; Petraroli, A.; Carucci, L.; Mormile, I.; Oliveti, M.; Bruno Morelli, M.; Fiordelisi, A.; Spadaro, G.; Campiglia, P.; Sala, M.; Trimarco, B.; Iaccarino, G.; Santulli, G.; Ciccarelli, M.. - In: HYPERTENSION. - ISSN 0194-911X. - 76:5(2020), pp. 1625-1636. [10.1161/HYPERTENSIONAHA.120.15130]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/827129
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