Supplemental Digital Content is available in the text. 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.

中文翻译：

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内皮 G 蛋白偶联受体激酶 2 在血管性水肿中的作用

补充数字内容在文本中可用。过度的 BK（缓激肽）刺激是导致血管性水肿中内皮过度通透的原因。然而，尚未研究这些反应背后的分子机制。BK 受体是被 GRK2（G 蛋白偶联受体激酶 2）磷酸化的 Gq 蛋白偶联受体，具有迄今为止未知的生物学和病理生理学意义。在本研究中，我们试图通过调节 BK 信号来确定 GRK2 在血管性水肿中的功能作用。我们发现 BK 诱导的内皮细胞中胞质 Ca2+ 的积累对 GRK2 活性敏感，因为它通过抑制激酶显着增加。因此，BK 诱导的通透化和 NO 产生也增强了。体内，内皮中 GRK2 水平降低的小鼠 (Tie2-CRE/GRK2fl+/fl-) 在血管通透性和外渗方面对 BK 的反应增加。最后，GRK2 水平降低的患者表现出严重的血管性水肿表型。总之，这些发现将 GRK2 确立为 BK 信号传导的新型关键调节剂，在血管通透性和血管性水肿的病理生理学中具有重要作用。