MEA Research Review: Altered Endothelial Function in ME/CFS Blood Plasma

June 18, 2021

A recent publication by Blauensteiner et al. based in Austria has examined molecules which help make proteins (mircroRNAs) in the layer of cells lining blood vessels (endothelium). The results of this and of similar studies may help to provide biomarkers for use in the future diagnosis of ME/CFS.

How are these researchers connected to ME/CFS?

Dr. Westermeier comments that, “doing research on ME/CFS has also given us the possibility to establish close contact with CFS-Hilfe Österreich, an Austrian-wide contact point for people suffering from ME/CFS. They have supported our grant applications (ME Research UK & Solve ME/CFS Initiative) by reinforcing the need for funding this largely neglected disease in Austria.

“As a research group, we are convinced that engaging patients and their families as partners in the research process will lead to better clinical outcomes. Thus, patient-oriented research addressing their experiences and priorities will be certainly considered to conduct our next ME/CFS-related studies.”

Dr. Westermeier

What do we know about endothelial dysfunction in ME/CFS?

Recent clinical evidence (Scherbakov et al., 2020; Sørland et al., 2021) has placed endothelial dysfunction as another piece in the complex ME/CFS jigsaw. However, no studies had investigated the cellular mechanisms that modulate endothelial function, particularly the production of nitric oxide (NO), and if they are altered in ME/CFS.

Cross-section of a blood vessel

NO is a gas released by the endothelium, a layer of cells lining blood vessels, responsible for modulating the blood flowing throughout the body. Endothelial cells actively regulate the immune system, and NO helps to regulate blood and oxygen supply throughout the body.

Endothelial dysfunction is linked to inflammation and oxidative stress which can be caused by inadequate NO production. It is thought that vascular abnormalities such as these could play a part in the complex pathophysiological nature of ME/CFS.

Samples used in this study were provided by the UK ME/CFS Biobank (UKMEB) – see below –and included 28 mild/moderate patients and 30 severely affected patients. These were age-matched to 29 healthy controls.

What are the main findings of this study?

Blauensteiner et al. report that a set of well-described circulating markers used to modulate the production of NO is altered in plasma from ME/CFS patients.

The levels of five microRNAs (miRs) were altered in ME/CFS patients compared to healthy controls. miRs have been found to be altered in many diseases (such as cardiovascular disease) and have been proposed as biomarkers allowing the ability to predict, diagnose and monitor disease.

The set of miRs analysed in this study have been reported to decrease the NO production in endothelial cells. Results show that miR-21, miR-34a, miR-92a, miR-126, and miR-200c are all increased in ME/CFS patients compared to healthy controls.

These findings reinforce clinical evidence reporting decreased NO production in a subset of people with ME/CFS measured by flow-mediated dilatation (FMD) and/or peripheral arterial tonometry (EndoPAT).

By using plasma samples provided by the UK ME/CFS Biobank, the findings suggest that endothelial dysfunction might be a trait observed in a subset in approximately 40 to 60% of the ME/CFS population.

What are the implications from this research?

The authors propose that combining this set of circulating markers along with clinical evaluation might allow a more sensitive characterisation of endothelial function in people with ME/CFS.

The results are significant as they demonstrate that endothelial dysfunction (ED)-related miRs are observed in up to 60% of the ME/CFS population. This is in line with clinical evidence reporting that ED might be a trait observed in a subset (up to 40-50%) of the ME/CFS population (Scherbakov et al. 2020; Sørland et al. 2021).

What is the diagnostic value of these results?

The authors propose that a combination of clinical evaluation of endothelial function using assessment methods of FMD and/or EndoPAT, along with the detection of a set of circulating miRs, might allow a more sensitive characterization of ED in a subset of ME/CFS patients, which could help to provide an objective diagnostic test for the disease.

Why would problems with the blood vessels cause ME/CFS symptoms and disability?

Blood vessels regulate the vascular tone and, consequently, enable an adequate source of nutrients and oxygen to supply tissues throughout the body. Accordingly, due to their physiological relevance, impaired endothelial function might correlate with the well-known symptoms in ME/CFS such as chronic fatigue, and post-exertional malaise, for example.

What are the next steps from the findings in this research?

Currently, the research group led by Dr. Westermeier at FH Joanneum (Graz, Austria) is moving forward by evaluating in vitro (experimental work performed outside of a living organism such as in a test tube) whether endothelial cells exposed to plasma from the same cohort of people with ME/CFS exhibit impaired NO production. This approach aims to provide new evidence about the impact of endothelial function on ME/CFS at the cellular level.

Dr. Westermeier’s group are now focused on confirming their recent results by looking at whether the cellular/metabolic mechanisms that control NO production are altered in ME/CFS. Since their previous findings involved plasma samples from a British cohort of ME/CFS patients, the next grant applications will not only aim to increase cohort size but will also include people who have the disease in Austria.

Is there are link to Long-COVID?

There is a growing body of research evidence that associates Long-COVID with impaired endothelial function. Future research needs to consider the role of viral infections in NO production and the extent to which infections are involved in the development and maintenance of symptoms associated with ME/CFS.

What is the UK ME/CFS Biobank (UKMEB)?

The UKMEB was launched in August 2011 with funding and input from the ME Association (MEA), Action for M.E. and ME Research UK.  The MEA Ramsay Research Fund has continued to provide annual grants since 2011 and now covers all the basic running costs of this vital and unique project.

The UKMEB contains samples from mild to severely affected people aged 18-60 , as well as healthy controls and people with multiple sclerosis (MS). Blood samples have been aliquoted into serum, plasma, peripheral blood mononuclear cells (PBMC), red blood cells/granulocyte pellet, whole blood, and RNA. They use the samples in their own research and provide them to research teams from around the world. More information on this ME Association funded project can be found here.

Acronyms used in this review

ECEndothelial cells
EDEndothelial dysfunction
EndoPATPeripheral arterial tonometry
FMDFlow-mediated dilatation
NONitric oxide

Image credit: 123RF/alexmit

Katrina Pears, Research Correspondent, ME Association

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