Molecular mechanisms of bradykinin-induced angioedema
18 April 2018 (online)
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).
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.
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.
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.