Extracellular vesicles modulate endothelial nitric oxide production in patients with β-thalassaemia/HbE

Thrombosis is a significant complication in patients with β-thalassaemia/haemoglobin E (HbE), particularly in splenectomised patients. The endothelium is a key regulator of vascular haemostasis and homeostasis, through the secretion of various regulatory molecules. Nitric oxide (NO), produced by endothelial cells (ECs), regulates vascular functions by acting as a potent vasodilator and an inhibitor of platelet activation. Decreased NO bioavailability, a marker of vascular dysfunction, could be a contributing factor leading to thrombosis. Microparticles or medium extracellular vesicles (mEVs) are associated with thrombosis and vasculopathy in various diseases. Furthermore, elevated levels of mEVs have been observed in splenectomised patients with β-thalassaemia/HbE and could induce the expression of coagulation proteins, inflammatory cytokines and adhesion molecules in ECs. However, the effects of mEVs on NO regulation by ECs is currently unclear. In the present study, mEVs obtained from splenectomised patients with β-thalassaemia/HbE had significantly decreased NO production in human pulmonary artery ECs without affecting endothelial nitric oxide synthase expression or phosphorylation. Decreased NO production was attributed to increased haemoglobin levels in mEVs from splenectomised patients, leading to enhanced NO scavenging. These findings highlight a mechanism whereby haemoglobin-carrying mEVs directly scavenge NO, contributing to vascular dysfunction in β-thalassaemia/HbE disease.