Anaphylatoxin C3a induces vasoconstriction and hypertension mediated by thromboxane A2 in mice

Abstract

IntroductionSeveral recent reports indicate a marked crosstalk between innate immunity and vasoregulation. Anaphylatoxins C3a and C5a have been reported to induce vasoactive effects, but the mechanism of their actions is obscure. Earlier studies reported increased plasma levels of C3 in cardiovascular diseases, especially pulmonary hypertension. Therefore, complement activation may contribute to changes of the vascular tone and reactivity under pathophysiological conditions. In our present study we investigated the effects of C3a, the activate cleavage product of the most abundant complement protein of the human circulation, on the arterial tone and blood pressure as well as the signaling pathways involved.Materials and methodsThoracic aortic segments were isolated from adult male C57Bl/6 wild type (WT) and knockout (KO) mice deficient in either thromboxane prostanoid receptor (TP KO) or cyclooxygenase 1 (COX1 KO). Isometric tension changes of vascular segments were measured via myography. We studied the effects of C3a by using C3a (63–77) peptide fragment, a specific C3a receptor agonist. Vascular responses were quantitated as percent of reference contraction induced by 124 mM K+. In addition, we performed experiments monitoring blood pressure (BP) changes in vivo. In these experiments zymosan (30 mg/kg, i.v.), a direct complement activator was administered intravenously, after cannulation of carotid artery and jugular vein in anesthetized (pentobarbital, 90 mg/kg i.p.) mice. Blood samples were taken from other groups of WT mice and plasma TXB2 levels were measured 5 minutes after treatment with saline or zymosan.ResultsC3a (63–77) evoked a pronounced vasoconstriction in WT vessels (33±5%), which effect remained unaltered in the absence of endothelium (37±7%). The vessels of COX1 KO mice showed a decreased response (10±2%), and the C3a fragment caused a similarly reduced constriction in TP KO vessels (4±1%). In our in vivo experiments the administration of zymosan led to an increase of BP in WT mice (with an average of 14±5 mmHg), whereas causing a drop of 22±3 mmHg in TP KO mice's BP. In accordance, zymosan caused a two‐fold increase in the plasma level of thromboxane B2 in WT animals.ConclusionsOur experiments showed, that C3a (63–77) causes vasoconstriction in a non‐endothelium‐dependent manner, and this effect is mediated by COX1 and TP. These results propose that C3a‐mediated vasoconstriction is mediated by smooth muscle derived thromboxane A2. In addition, C3a (63–77) induce hypertension, which is also mediated by thromboxane A2. These results altogether indicate that C3a is involved in the regulation of vascular tone and/or reactivity via stimulating thromboxane A2 release.Support or Funding InformationGrant support: Semmelweis Research and Innovation Fund (STIA‐M‐17); Ministry of Human Capacities of Hungary (ÚNKP‐18‐2‐I‐SE‐12, FIKP‐2018 and EFOP‐3.6.3‐VEKOP‐16‐2017‐00009) and the Hungarian NRDIO (OTKA K‐115623, K‐125174 and NVKP_16‐1‐2016‐0042)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.