Marion Bisha1, Vu Thao-Vi Dao1,2, Ehsan Gholamreza-Fahimi1, Michael Vogt3, Marc van Zandvoort3,4, Sarah Weber1, Murat Bas5, Farbod Khosravani1, Georg Kojda1, Tatsiana Suvorava1,6. 1. Institute of Pharmacology and Clinical Pharmacology, Heinrich Heine University, Düsseldorf, Germany. 2. Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. 3. Interdisciplinary Centre for Clinical Research, Rheinisch-Westfälische Technische Hochschule Aachen, University Hospital, Aachen, Germany. 4. Department of Genetics and Cell Biology, Sector Molecular Cell Biology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. 5. Department of Otorhinolaryngology, Technical University of Munich, Munich, Germany. 6. Cardiovascular Research Laboratory, Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Düsseldorf, Germany.
Abstract
BACKGROUND AND PURPOSE: Non-allergic angio-oedema is a life-threatening disease mediated by activation of bradykinin type 2 receptors (B2 receptors). The aim of this study was to investigate whether activation of B2 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. EXPERIMENTAL APPROACH: We generated a new transgenic mouse model characterized by endothelium-specific overexpression of the B2 receptor (B2tg ) and established a non-invasive two-photon laser microscopy approach to measure the kinetics of spontaneous extravasation in vivo. The B2tg mice showed normal morphology and litter size as compared with their transgene-negative littermates (B2n ). KEY RESULTS: Overexpression of B2 receptors was functional in conductance vessels and resistance vessels as evidenced by B2 receptor-mediated aortic dilation to bradykinin in presence of non-specific COX inhibitor diclofenac and by significant hypotension in B2tg respectively. Measurement of dermal extravasation by Miles assay showed that bradykinin induced extravasation was significantly increased in B2tg as compared with B2n . However, neither endothelial overexpression of B2 receptors nor treatment with the ACEi moexipril or B2 antagonist icatibant had any effect on spontaneous extravasation measured by two-photon laser microscopy. CONCLUSIONS AND IMPLICATIONS: Activation of B2 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.
BACKGROUND AND PURPOSE:Non-allergic angio-oedema is a life-threatening disease mediated by activation of bradykinin type 2 receptors (B2 receptors). The aim of this study was to investigate whether activation of B2 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. EXPERIMENTAL APPROACH: We generated a new transgenic mouse model characterized by endothelium-specific overexpression of the B2 receptor (B2tg ) and established a non-invasive two-photon laser microscopy approach to measure the kinetics of spontaneous extravasation in vivo. The B2tg mice showed normal morphology and litter size as compared with their transgene-negative littermates (B2n ). KEY RESULTS: Overexpression of B2 receptors was functional in conductance vessels and resistance vessels as evidenced by B2 receptor-mediated aortic dilation to bradykinin in presence of non-specific COX inhibitor diclofenac and by significant hypotension in B2tg respectively. Measurement of dermal extravasation by Miles assay showed that bradykinin induced extravasation was significantly increased in B2tg as compared with B2n . However, neither endothelial overexpression of B2 receptors nor treatment with the ACEi moexipril or B2 antagonist icatibant had any effect on spontaneous extravasation measured by two-photon laser microscopy. CONCLUSIONS AND IMPLICATIONS: Activation of B2 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.
Authors: R Golser; A C Gorren; A Leber; P Andrew; H J Habisch; E R Werner; K Schmidt; R C Venema; B Mayer Journal: J Biol Chem Date: 2000-02-25 Impact factor: 5.157
Authors: Marc Oppermann; Tatsiana Suvorava; Till Freudenberger; Vu Thao-Vi Dao; Jens W Fischer; Martina Weber; Georg Kojda Journal: Basic Res Cardiol Date: 2011-02-06 Impact factor: 17.165
Authors: Marion Bisha; Vu Thao-Vi Dao; Ehsan Gholamreza-Fahimi; Michael Vogt; Marc van Zandvoort; Sarah Weber; Murat Bas; Farbod Khosravani; Georg Kojda; Tatsiana Suvorava Journal: Br J Pharmacol Date: 2018-04-14 Impact factor: 8.739