B₁- and B₂-bradykinin receptors modulate endothelial cell-cell-contacts in contrary ways

Introduction Hereditary angioedema is a rare genetic disorder characterized by recurrent swelling attacks. These can affect the entire body, with laryngeal edema being potentially fatal. Edema are mediated by bradykinin, which binds to specific receptors (B₁R and B₂R). This leads to a disruption of endothelial barrier function, which is ensured by tight- and adherens-junctions. However, the exact role of the respective receptors in this barrier dysfunction is still poorly understood.

Materials and methods Human umbilical vein endothelial cells were cultured on transwell filters and examined for their barrier function by determing transendothelial resistance (TEER) and apparent permeability coefficient (P_app). The respective bradykinin receptors were specifically pharmacologically activated or blocked. Semi-quantitative RT-PCR, western blots and immunofluorescence were used to detect changes in the expression and localization of tight- and adherens-junction proteins.

Results Activation of B₂R resulted in a decrease of TEER with a concomitant increase in P_app. This was accompanied by decreased expression of tight- and adherens-junction proteins at mRNA and protein levels. This effect could be inhibited by simultaneous activation of B₁R.

Conclusion Activation of the B₂R results in increased paracellular permeability of endothelial cells. This is mediated by a modulation of tight- and adherens-junction proteins. In contrast, simultaneous activation of the B₁R prevents this effect. These results reveal previously unexplored new aspects in the pathophysiology of bradykinin-mediated angioedema.