Institute of Pharmacology and Clinical Pharmacology, Heinrich Heine University, Düsseldorf, Germany.
Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
Br J Pharmacol. 2018 May;175(10):1607-1620. doi: 10.1111/bph.14166. Epub 2018 Apr 14.
Non-allergic angio-oedema is a life-threatening disease mediated by activation of bradykinin type 2 receptors (B receptors). The aim of this study was to investigate whether activation of B receptors by endogenous bradykinin contributes to physiological extravasation. This may shed new light on the assumption that treatment with an angiotensin converting enzyme inhibitor (ACEi) results in an alteration in the vascular barrier function predisposing to non-allergic angio-oedema.
We generated a new transgenic mouse model characterized by endothelium-specific overexpression of the B receptor (B2 ) and established a non-invasive two-photon laser microscopy approach to measure the kinetics of spontaneous extravasation in vivo. The B2 mice showed normal morphology and litter size as compared with their transgene-negative littermates (B2 ).
Overexpression of B receptors was functional in conductance vessels and resistance vessels as evidenced by B receptor-mediated aortic dilation to bradykinin in presence of non-specific COX inhibitor diclofenac and by significant hypotension in B2 respectively. Measurement of dermal extravasation by Miles assay showed that bradykinin induced extravasation was significantly increased in B2 as compared with B2 . However, neither endothelial overexpression of B receptors nor treatment with the ACEi moexipril or B antagonist icatibant had any effect on spontaneous extravasation measured by two-photon laser microscopy.
Activation of B receptors does not appear to be involved in spontaneous extravasation. Therefore, the assumption that treatment with an ACEi results in an alteration in the physiological vascular barrier function predisposing to non-allergic angio-oedema is not supported by our findings.
非过敏性血管性水肿是一种由缓激肽 2 型受体（B 受体）激活介导的危及生命的疾病。本研究旨在探讨内源性缓激肽激活 B 受体是否有助于生理渗出。这可能为这样一种假设提供新的线索，即血管紧张素转换酶抑制剂（ACEi）的治疗会改变血管屏障功能，从而导致非过敏性血管性水肿。
我们生成了一种新的转基因小鼠模型，其特征为内皮细胞特异性过表达 B 受体（B2），并建立了一种非侵入性的双光子激光显微镜方法来测量体内自发性渗出的动力学。与转基因阴性的同窝仔鼠（B2）相比，B2 仔鼠表现出正常的形态和同窝仔鼠数量。
B 受体的过表达在传导血管和阻力血管中是功能性的，这表现在存在非特异性 COX 抑制剂双氯芬酸的情况下，B 受体介导的主动脉对缓激肽的扩张以及 B2 中显著的低血压。Miles 测定法测量的皮肤渗出表明，与 B2 相比，缓激肽诱导的渗出在 B2 中显著增加。然而，内皮细胞过表达 B 受体或用 ACEi 莫昔普利或 B 拮抗剂依替巴肽治疗均对双光子激光显微镜测量的自发性渗出无影响。
B 受体的激活似乎不参与自发性渗出。因此，我们的发现不支持 ACEi 治疗会改变生理血管屏障功能从而导致非过敏性血管性水肿的假设。
