Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical  studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we  have recently reported altered ED-related microRNAs in plasma from affected  individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial  isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major  cause of ED. In this study, we hypothesized that plasma from that cohort of  ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human  umbilical vein endothelial cells (HUVECs) in the presence of plasma from either  ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12).  Then, we measured the NO production in the absence and presence of tyrosine  kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively),  well-known to activate eNOS in ECs. Our data showed that HUVECs incubated with  ME/CFS-plasma produced less NO either in the absence or presence of eNOS  activators compared to ones in presence of HC-plasma. Also, the NO production  elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more  affected than the one triggered by insulin (TKR agonist). Finally, inhibitory  eNOS phosphorylation at Thr(495) was higher in HUVECs treated with ME/CFS-plasma  compared to the same treatment with HC-plasma. In conclusion, this study in vitro  shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients,  suggesting an unreported role of eNOS in the pathophysiology of this disease.