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DOI: 10.1055/s-0038-1639742
Molecular mechanisms of bradykinin-induced angioedema
Introduction:
Angioedema is a known adverse effect of renin-angiotensin-aldosterone system blockers. It is characterized by non-inflammatory swelling of the head and neck region, and increased plasma and tissue levels of bradykinin (BK). In-depth elucidation of bradykinin-dependent mechanisms of microvascular destabilization are still needed to comprehend the molecular pathways causing angioedema and for rational design of anti-edematous therapy. Therefore, BK-induced changes in endothelial permeability and cellular architecture were investigated in a model of human dermis microvasculature (HDMECs).
Methods:
Macromolecular tracer assays were used to examine BK-induced permeability changes in primary HDMECs. BK-induced modulation of cell-to-cell junctional proteins expression were investigated by western blot, qRT-PCR and microscopy. BK receptor 2 down-stream signalling was investigated by calcium imaging and cGMP/cAMP ELISA. Finally, vascular hyperpermeability target genes were determined by qRT-PCR.
Results:
It was found that BK acute stimulation increases HDMECs permeability to macromolecules, results in down-regulation of claudin 5 expression and increment of phosphorylated VE-Cadherin pool. These effects were diminished in presence of BK 2 receptor antagonist, HOE 140. Release of intracellular calcium initiates down-stream signalling cascade, which further results in up-regulation of Ang-2 and VEGF expression.
Conclusion:
BK acute stimulation alters the endothelial barrier function, increasing the permeability to macromolecules and affecting the stability of cellular tight- and adherens- junctions. Furthermore, it results in up-regulation of angiopoietins and vascular endothelial growth factors expression thus promoting vascular homeostasis destabilization.
No conflict of interest has been declared by the author(s).
Publication History
Publication Date:
18 April 2018 (online)
© 2018. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Georg Thieme Verlag KG
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