Novel Vasoregulatory Aspects of Hereditary Angioedema: the Role of Arginine Vasopressin, Adrenomedullin and Endothelin-1

Abstract

The elevation of bradykinin (BK) level during attacks of hereditary angioedema due to C1-Inhibitor deficiency (C1-INH-HAE) is well known. We previously demonstrated that endothelin-1 (ET-1) level also increases during C1-INH-HAE attacks. Although BK and ET-1 are both potent vasoactive peptides, the vasoregulatory aspect of the pathomechanism of C1-INH-HAE has not yet been investigated. Hence we studied the levels of vasoactive peptides in controls and in C1-INH-HAE patients, as well as evaluated their changes during C1-INH-HAE attacks. The levels of arginine vasopressin (AVP), adrenomedullin (ADM) and ET-1 were measured in the plasma of 100 C1-INH-HAE patients in inter-attack periods and of 111 control subjects, using BRAHMS Kryptor technologies. In 18 of the 100 C1-INH-HAE patients, the levels of vasoactive peptides were compared in blood samples obtained during attacks, or in inter-attack periods. AVP, ADM and ET-1 levels were similar in inter-attack samples from C1-INH-HAE patients and in the samples of controls, although cardiovascular risk has an effect on the levels of vasoactive peptides in both groups. The levels of all three vasoactive peptides increased during C1-INH-HAE attacks. Moreover, the levels of ET-1 and ADM as well as their changes during attacks were significantly correlated. This study demonstrated that vascular regulation by vasoactive peptides is affected during C1-INH-HAE attacks. Our results suggest that the cooperation of several vasoactive peptides may be necessary to counterbalance the actions of excess BK, and to terminate the attacks. This may reveal a novel pathophysiological aspect of C1-INH-HAE.

The central role of endothelium in hereditary angioedema due to C1 inhibitor deficiency

“…Differently from the above-mentioned mediators, levels of endothelin-1 and arginine vasopressin, peptides derived respectively from endothelium and hypothalamus, both of which show vasoconstrictor activity, were found to be not different in C1-INH-HAE as compared to the normal control [66]. During an acute HAE attack endothelin-1 and arginine vasopressin increase and could theoretically have a role to counterbalance BK activity [66]; adrenomedullin, broadly expressed peptide, has vasodilatory activity but counteracts the BK-driven vasopermeabilization, and is found elevated as well during attacks [66].…”

“…Since BK tends to be increased in plasma of C1-INH-HAE patients, as shown by the evidences exposed of HK consumption even during remission phase [63], a homeostasis-preserving mechanism could be hypothesized, leading to enhanced vasoconstriction and increased release of anti-permeability factors in plasma of C1-INH-HAE patients, in order to counteract BK activity. Surprisingly, as explained into details in the following paragraph, vascular endothelial growth factors (VEGF-A, VEGF-C), Angiopoietin 1 (Angpt1) and 2 (Angpt2), adrenomedullin and phospholipase A2 (PLA 2 ), all known to drive vasodilation and permeabilization, were found to be increased in intercritical phases [65][66][67][68].…”

Oxidative stress markers in patients with hereditary angioedema

“…C1-INH-HAE is associated with dysregulation of complement, coagulation, and contact cascades [44], and high levels of procoagulant and fibrinolytic activity have been demonstrated in patients during acute attacks and remissions [45, 46]. Thus, the different behavior observed between C1-INH-HAE patients and FXII-HAE patients may be related to a different imbalance in the coagulation, contact and kinin pathways [47, 48]. The oxidation of fibrinogen plays a key role in the formation of AOPPs, which, in turn, may promote functional alterations in fibrinogen, increasing its procoagulant activity or modifying its direct effects on vascular tone [49, 50].…”

Biomarkers in Hereditary Angioedema

“…As the endothelium is inherently related to microvascular permeability and, in consequence, the swelling phenomenon, it represents another area of interest regarding potential biomarkers in HAE. Studies in this field involved vascular endothelial cadherin (transmembrane adhesive protein) [ 72 , 76 ], von Willebrand factor (marker of endothelial damage), soluble E-selectin (cytokine-induced adhesion molecule), endothelin-1 (vasomotor activity regulator) [ 30 , 77 , 78 ], arginine vasopressin , adrenomedullin [ 78 ], atrial natriuretic peptide [ 79 ], as well as endothelial-derived endocan and vascular cell adhesion molecule-1 (markers of endothelial function) [ 80 ]. The subsequently studied modulators of vascular permeability included vascular endothelial growth factors , angiopoietin-1 (which promotes endothelial stabilization) and angiopoietin-2 (which facilitates vascular permeability) [ 81 , 82 ], secreted phospholipases A2 (particularly the 2A group) [ 83 ], and platelet-activating factor acetylhydrolase [ 81 ].…”