Molecular Dambusters: What Is Behind Hyperpermeability in Bradykinin-Mediated Angioedema?

Abstract

In the last few decades, a substantial body of evidence underlined the pivotal role of bradykinin in certain types of angioedema. The formation and breakdown of bradykinin has been studied thoroughly; however, numerous questions remained open regarding the triggering, course, and termination of angioedema attacks. Recently, it became clear that vascular endothelial cells have an integrative role in the regulation of vessel permeability. Apart from bradykinin, a great number of factors of different origin, structure, and mechanism of action are capable of modifying the integrity of vascular endothelium, and thus, may participate in the regulation of angioedema formation. Our aim in this review is to describe the most important permeability factors and the molecular mechanisms how they act on endothelial cells. Based on endothelial cell function, we also attempt to explain some of the challenging findings regarding bradykinin-mediated angioedema, where the function of bradykinin itself cannot account for the pathophysiology. By deciphering the complex scenario of vascular permeability regulation and edema formation, we may gain better scientific tools to be able to predict and treat not only bradykinin-mediated but other types of angioedema as well.

Keywords: Angioedema; Bradykinin; Endothelial cells; Pathomechanism; Permeability.

Fig. 1

Main features of tissue edema. Pathophysiology, location, and temporal relations are the main features of edema. A few examples are also included under “pathophysiology.” Color shading highlights the main topic of the current review—the vascular endothelium

Fig. 2

Common intercellular signaling events of endothelial permeability regulation. The most important signaling events leading to barrier protection (tight junction and adherent junction stabilization, formation of cortical actin network) are emphasized by green color, whereas those leading to barrier disruption and hyperpermeability (phosphorylation and dissociation of cell junction components, phosphorylation of myosin light chain and formation of actin stress fibers) by red color

Fig. 3

Characteristics of endothelial permeability regulation in different tissues. The brain, skin and liver are shown as examples. The green area indicates normal activity, whereas the red area indicates pathological intensity of paracellular transport. Gray areas on the dials indicate zone of permeability that is rarely reached even in pathological conditions (never or very few times during a lifetime). Note that skin microvasculature becomes frequently hyperpermeable (indicated by red line without grey area) during a normal lifespan (e.g., in response to minor traumas, mosquito bites, allergic reactions, etc.)

Fig. 4

Proposed mechanisms of common trigger-factors of angioedema attacks. The figure shows the most important mechanisms by which trigger factors of hereditary angioedema exert their vascular permeability effects on endothelial cells

Fig. 5

Role of endothelial signal integration in the permeability response. Predisposing mutations and genetic background together with ever-changing factors (i.e., drugs, lifestyle, and trigger-factors) act on endothelial cells, which integrate these signals. The output of this signal integration (i.e., controlled hyperpermeability or uncontrolled edema) could only be estimated if each of these signals were fully known