Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients, Bertinat et al (2022)

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

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.

https://www.sciencedirect.com/science/article/abs/pii/S1537189122000027

 

Could this explain why I felt so much better last summer? I made an effort to get a good dose of sunlight every day. At first this was unpleasant because it induced dizziness and weakness but then my body seemed to adjust to it. I improved so much that on the best days I was able to walk uphill in the heat for an hour with only very mild consequences. I also went swimming often which seemed to have a positive effect on circulation. Now in the winter I have deteriorated to a level where even a 10 minute walk risks aggravating symptoms and fatigue is disabling.

(sunlight triggers nitric oxide production)

 

Francisco Westermeier, one of the researchers, has written a summary on Twitter:

 

For the most part, I get a good dose of sunlight everyday during the summer, however, it has never caused me to feel better.

 

@SNT Gatchaman

They say it’s unexpected but I have seen eNOS come up at least once in the ME literature. This is a novel mechanism though. I’m interested to see how this gels with some of the leading endothelial dysfunction theories.

 

So, if this lead to inadequate vasodilation in the microcirculation (perhaps while under the "load" of exercise) might it lead to effects like the arteriovenous "shunting" that Dr. Systrom has hypothesized?

Also, I don't know if you wind up with "vasoconstriction" when vasodilation is inhibited, but might a "slight" system wide vasoconstriction result in some measurable reduction in blood volume?

 

basic questions

what kind of endothelial dysfunction is found or hypothesized in m.e.?

what are the signs and symptoms of endohelialdysnction thtat might befund? raynauds? o2 transport? angioedema?

does taking vit d3 inrease no or must it be sunlight

 

Hi Samuel, this is a 12 patient in vitro hypothesis-driven experiment and nothing was mentioned about vitamin D; it is best not to get too carried away. It would need to be replicated and debated to understand the meaning.

Endothelial dysfunction is when the veins do not constrict properly to send blood back to the heart. It is believed that endothelial dysfunction is associated with POTS and dysautonomia.

 

I think that in the ME/ POTS population vasodilation is the problem- i was trying to explain our context.

 

Looks like this has just been made open access, for those who want to read the whole thing.

 

I've felt better every time I went for a walk with my brother and his kids, whilst it's supposed to make me feel worse for overexerting somewhat. I wouldn't recommend people trying to go out and go over their limits, but last summer was a good one, where I went out a number of times and felt better for it. Usually when I do PEM makes me sick for days.

 

This theory (endothelial / vessel dysfunction) makes sense to me. If the micro blood vessels are constricted, then not enough oxygen would get to tissues like the nerves and muscles. This would then lead to fatigue and rapid fatiguability. PEM could simply be an after effect of oxygen deprivation during times of stress.

Furthermore, this theory might explain why most of the cellular studies have been inconclusive and / or not convincing. Namely, if the problem is in the vessels and not the cells then in-vitro cellular studies would not detect it.

 

But would it lead to delayed PEM?

 

Maybe it is possible. I don't think there has been much or any research on how cells react to low level hypoxia or reduced micro-circulation. It could simply be that the damage takes some time to present itself.

 

I think this is the study they're referring to, by the same team:

https://www.s4me.info/threads/alter...-cfs-patients-2021-blauensteiner-et-al.20598/

 

Can this also be the cause of POTs patients having extra severe symptoms after showering?

 

Hi @Sizzle it looks like it’s your first post, so welcome!
The vasodilatation of the vessels is well known as a problem and having severe symptoms following a shower is common. It is suggested you sit (as opposed to stand) and to not set the water temp too high. I also wrap myself with towels after the shower and sit until i dry, but if you feel dizzy or short of breath, you should really lay down.

 

Its interesting, empirical and quantitative, the question is whether it is replicable?