Role of Endothelial G Protein-Coupled Receptor Kinase 2 in Angioedema

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.

miR-24 Targets the Transmembrane Glycoprotein Neuropilin-1 in Human Brain Microvascular Endothelial Cells

“…Several investigators have demonstrated that Neuropilin-1 is involved in EC permeability [ 35 , 36 , 37 ]. To assess the functional role of miR-24 on Neuropilin-1 mediated endothelial permeability, we performed an in vitro permeability assay, following an experimental protocol that we have recently described [ 34 ].…”

“…The in vitro permeability assay was performed as we previously described [ 34 ]. Briefly, hBMECs transfected with miR-24 mimic or miR scramble were grown on 0.4-mm fibronectin-coated (R&D Systems, Inc., Minneapolis, MN, USA) Transwell filters (Corning Inc., Corning, NY, USA).…”

miR-24 targets SARS-CoV-2 co-factor Neuropilin-1 in human brain microvascular endothelial cells: Insights for COVID-19 neurological manifestations

“…The in vitro permeability assay was performed as we previously described [34]. Brie y, hBMECs transfected with miR-24 mimic or miR scramble were grown on 0.4-mm bronectin-coated (R&D Systems) Transwell lters (Corning Inc., Corning, NY, USA).…”

The Metabolic Role of GRK2 in Insulin Resistance and Associated Conditions

“…G Protein-Coupled Receptor Kinases (GRK) are known to phosphorylate G Protein Coupled Receptors GPCRs on the plasma membrane to turn off their intracellular signaling [ 24 , 25 ]. Therefore, GRKs exert a critical role in both physiological states and pathological conditions that are mainly associated with alterations of the adrenergic signaling.…”