R Bertinat, R Villalobos-Labra, L Hofmann, J Blauensteiner, N Sepúlveda, F Westermeier
Universidad de Concepción, Concepción, Chile; FH Joanneum University of Applied Sciences, Graz, Austria; and others
- Nitric oxide (NO) production was reduced in endothelial cells exposed to blood plasma from people with ME/CFS.
- Inadequate NO release is an important cause of the endothelial dysfunction which has been reported in a subgroup of patients.
- These findings therefore show the mechanisms potentially involved in the endothelial dysfunction that affects some people with ME/CFS.
This study was supported by ME Research UK and carried out using samples from the UK ME/CFS Biobank.
In their previous work, Dr Westermeier’s group analysed blood samples from people with ME/CFS, and found increased levels of five microRNAs, all of which are involved in control of the vascular endothelium and the generation of nitric oxide (NO).
The team has continued this work with a new article written by Dr Romina Bertinat (who is based at the University of Concepción in Chile) and published in the journal Vascular Pharmacology. And this time they have been looking more directly at the production of NO.
To recap, the endothelium is a layer of cells lining every blood vessel, and is involved in controlling their opening and closing, and hence the amount of blood flowing through them. This ensures an adequate supply of blood and oxygen to tissues throughout the body. An important way in which the endothelium regulates blood flow is through the release of NO.
NO therefore plays a critical role in maintaining a healthy cardiovascular system, and decreased production of NO is a characteristic of many diseases, including hypertension, diabetes and heart failure.
The aim of Dr Bertinat’s study was to investigate whether endothelial cells exposed to plasma from people with ME/CFS would be impaired in their ability to generate NO. (Plasma is the liquid portion of blood which carries red and white blood cells, and platelets.)
Endothelial cells were incubated with plasma from people with ME/CFS (obtained from the UK ME/CFS Biobank) or with plasma from healthy control subjects. The cells were then exposed to proteins that are known to stimulate the production of NO, including insulin, bradykinin, histamine and acetylcholine.
Importantly, the endothelial cells exposed to ME/CFS plasma generated significantly less NO than did the ones exposed to healthy plasma, and this was the case for all four of the stimulatory proteins tested.
Another important finding related to the enzyme responsible for producing NO in the endothelium. The activity of this enzyme (endothelial NO synthase) was also reduced in the presence of plasma from ME/CFS patients, raising the possibility that it may represent a target for treatment.
There are still questions about how these findings relate to the symptoms of ME/CFS, and Dr Westermeier discusses these issues in a recent interview with CureME (the team that runs the UK ME/CFS Biobank).
He suggests that impaired NO production might lead to defective vascular function following exercise, which could indicate a role for NO in post-exertional malaise. But NO is also involved in metabolism and the immune system, raising more intriguing possibilities.
For now, the team plans to look at several other biochemical pathways and metabolites involved in NO production, and we very much look forward to seeing what they uncover in the near future.
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 either plasma from ME/CFS patients (ME/CFS-plasma, n=11) or healthy controls (HC-plasma, n=12). Then, we measured the NO production in the absence or presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs. Our data show 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 Thr495 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.