Red blood cells from patients with pre-eclampsia induce endothelial dysfunction

Abstract

Rationale: Pre-eclampsia is a multisystem disorder associated with systemic vascular dysfunction and decreased nitric oxide (NO) bioactivity. Arginase competes with NO synthase (NOS) for l-arginine, and its upregulation may reduce NOS-derived NO formation or induce production of reactive oxygen species (ROS) via uncoupling of NOS, resulting in endothelial dysfunction. Red blood cells (RBCs) have emerged as key players in NO homeostasis via their interactions with the endothelium. Studies have demonstrated that abnormal RBC arginase function in patients with diabetes contributes to oxidative stress and endothelial dysfunction.

Aim: The aim of the study was to investigate if reduced NO bioavailability and increased ROS in pre-eclampsia is mediated via RBC-dependent mechanisms.

Methods: In this translational study, plasma and RBCs were isolated from gestationally matched pre-eclamptic and healthy pregnant women and co-incubated overnight with mouse aortas for vascular reactivity studies. NO bioactivity, that is, nitrate, nitrite and cGMP, was assessed in plasma. Arginase activity and expression were analysed in RBCs.

Results: Plasma markers of NO homeostasis and signalling were decreased in pre-eclamptic women vs. healthy pregnant women. Co-incubation of aorta with pre-eclamptic RBCs, but not healthy pregnant RBCs, induced endothelial dysfunction, which was ameliorated by pharmacological inhibition of arginase, scavenging of ROS, and by nitrite treatment. This pathological vascular phenotype was not observed following incubation with pre-eclamptic plasma. Arginase expression and activity in RBCs were increased in pre-eclamptic vs. healthy pregnant women and was associated with pre-eclampsia severity. Pre-eclamptic RBC-induced endothelial dysfunction was not because of increased haemolysis/cell-free haemoglobin.

Conclusion: This study demonstrates a novel role of the RBC in mediating the endothelial dysfunction associated with pre-eclampsia through arginase-dependent and oxidative stress-dependent mechanisms. Targeting of RBC arginase may provide a novel treatment modality for pre-eclampsia.