Controlled release of ATP from red blood cells (RBC) in response to mechanical deformation or hemoglobin desaturation is a key physiological process for matching oxygen supply with demand in both pulmonary and systemic tissues[8]. Released ATP binds to endothelial purinergic receptors and initiates signaling events that ultimately lead to increased vasodilator and/or decreased vasoconstrictor activity[9]; the net effect being increased blood flow.



Seminal studies over the last decade have mapped out elements of the signaling pathway in RBC that regulates ATP release and involves Gi-proteins, cAMP activation of PKA and key roles for CFTR and Pannexin proteins[8] and have done much to dispel the notion that RBC are ‘dead’ cellular bags whose sole function is to compartmentalize hemoglobin. Furthermore, dysfunction in this signaling pathway has been demonstrated in diabetic and pulmonary hypertensive patients with the concomitant loss of ATP dependent regulation of blood flow discussed as a possible mechanism underlying vascular complications that characterize these diseases​

This is super exciting. Blood cells that don't deform properly could be very relevant.I recently learned that one reason blood vessels relax is because when red blood cells go through tight points in the blood vessels, the red blood cells get squished and bumped, which causes them to release ATP, which acts as a vasodilatory signal. If the red blood cells don't squeeze when they go through tight points, becuas they are stiff, you won't get the vasodilation you need.(Another cause of vasodilation is that when vessels are too narrow for the amount of blood going through, the vessels get bumped and pushed by the blood cells. This is called shear stress. In response, they are supposed to relax, which they do by releasing Nitric oxide (NO). You will remember that Fluge and Mella patented an NO supplement for ME/CFS.)POTS is also related to problems with vasodilation and vasoconstriction, so there's clear evidence a lot of us have problems there.Vasodilation (blood vessels getting wider) is crucial for getting enough blood (and the oxygen it carries) to muscles which are working. Without sufficient blood flow, you could get tired very quickly, and maybe end up doing anaerobic respiration, causing lactic acid buildup. [hopefully this all sounds like it's fitting together!]Here's a good except of a paper from 2013 Incidentally, it's interesting this mentions purinergic signalling, which is Robert Naviaux's pet theory. However it seems like a specific case, rater than the generic case (sickness behaviour/winter metabolism) that Naviaux is pursuing. Open to hearing if anyone can see a linkage there.My personal case history suggests to me problems with vasodilation, because the things I can't stand are all things that would normally cause vasodilation - exercise, alcohol, warm weather, mental stress - and especially all of these at once. I also seem to do better with high iron supplementation. So I'm pretty interested in this hypothesis.