Preprint Shear Stress Tolerance Threshold, eNOS Uncoupling, and the Two-Threshold Model of [PEM] in [LC]: A Mechanistic Hypothesis [...], 2026, Karipidis et al

I see that laminar stress and oscillatory shear stress include the topics of senescence, autophagy, and STING.

Oscillatory shear stress promotes atherosclerosis via inducing STING activation. Activation of STING pathway induces endothelial cell senescence in atherosclerosis. Oscillatory shear stress mediating STING activation via mitochondrial DNA leakage.

In this study, we found that laminar shear stress(LSS) could inhibit the increased expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), and matrix metallopeptidase-9 (MMP-9) caused by TNF-α in an autophagy-dependent pathway in human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs). Whole-transcriptome sequencing analysis revealed that erythropoietin-producing hepatocyte receptor B2 (EPHB2) was a key gene in response to LSS. Moreover, co-immunoprecipitation assay indicated that LSS could enhance the EPHB2-mediated nuclear translocation of high mobility group box-1 (HMGB1), which interacts with Beclin-1 (BECN1) and finally leads to autophagy.

This tangent is interesting.
Oh, it's not a tangent! Senescence may be part of the vicious cycle.

Replicative Endothelial Cell Senescence May Lead to Endothelial Dysfunction by Increasing the BH2/BH4 Ratio Induced by Oxidative Stress, Reducing BH4 Availability, and Decreasing the Expression of eNOS​


Replicative Endothelial Cell Senescence May Lead to Endothelial Dysfunction by Increasing the BH2/BH4 Ratio Induced by Oxidative Stress, Reducing BH4 Availability, and Decreasing the Expression of eNOS - PMC

Vascular aging is associated with the development of cardiovascular complications, in which endothelial cell senescence (ES) may play a critical role. Nitric oxide (NO) prevents human ES through inhibition of oxidative stress, and inflammatory ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
 
A new study supported by PolyBio Research Foundation studied children and young adults with Long COVID, providing evidence linking endovascular inflammation, increased quantity and size of fibrin-amyloid “microclots,” and neutrophil activation, and finding detectable Spike protein in a subset. Published in Pediatric Research, the study helps clarify the biological basis of cardiovascular symptoms in an important but understudied Long COVID population, and advances scientific insights that will support future diagnostic development.

It seems it would be helpful to combine polybio's markers and @YiannisK's.

 
I really appreciate that @YiannisK's paper includes recommendations for remediation.

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I have heard good things about Sulodexide for repairing glycocalyx. It's not available in the States yet, but fucoidan could be used in it's place.

Here's a study about SARS-CoV-2 effect on glycocalyx.

Endothelial Glycocalyx Injury in SARS-CoV-2 Infection: Molecular Mechanisms and Potential Targeted Therapy​

 
Published as —

eNOS Uncoupling, Shear-Stress Tolerance, and the Two-Threshold Model of Post-Exertional Malaise in Long COVID: A Mechanistic Hypothesis With Implications for Physiotherapy and Recovery Protocols
Yiannis K Karipidis; Konstantinos Y Karipidis

OBJECTIVE
To propose and make testable a mechanistic hypothesis for post-exertional malaise (PEM) in a clinically distinct subset of Long COVID patients, in whom delayed exertional symptoms coexist with consistently normal macrovascular investigations.

METHODS
Established vascular-biology literature is synthesized into an integrated, falsifiable model centered on endothelial nitric oxide synthase (eNOS) uncoupling, from which mechanism-specific predictions and a dynamic pre-/post-exertion biomarker validation framework are derived.

RESULTS
We propose that SARS-CoV-2-induced endotheliitis activates inducible nitric oxide synthase and silently depletes the tetrahydrobiopterin (BH4) pool on return to activity, shear-stress activation of structurally intact eNOS against a depleted BH4 background yields superoxide rather than nitric oxide, generating peroxynitrite that sustains a self-amplifying nitro-oxidative cycle. The Two-Threshold Model distinguishes a PEM threshold from a shear-stress-tolerance threshold and predicts that prolonged immobility may paradoxically erode endothelial function. eNOS uncoupling is positioned as one node among alternative microvascular pathways, and autonomic findings are proposed to be secondary within this phenotype.

CONCLUSIONS
This phenotype-specific, falsifiable hypothesis yields mechanism-derived predictions and rehabilitation implications consistent with symptom-contingent pacing guidance; it does not claim to explain all Long COVID presentations.

Web | DOI | PDF | Microcirculation | Open Access
 
Jonathan Edwards said:
OK, so it isn't endotheliitis.


You mean the fashion of the Twitterati has gone that way I guess. I am afraid I am a rather old hand at biomedical scepticism. I have read more bullshit than you have had hot dinners!


Well if you cannot detect any hypoperfusion, how do you know it is there? Hypoperfusion makes your skin change colour. That doesn't happen in Long Covid. I am afraid I dont believe a word of it. Pathobiology that isn't there isn't there.



I know all about shear forces and NO and all that but I don't see any dots joining up here I am afraid. And if you want to join dots I think you would do better to avoid pseudoconcepts like endotheliitis. Biomedical science, like Guness, has always had a bit of useless froth on the top. Unfortunately, these days, my impression is that the froth fills most of the glass. I am only interested in the black stuff.
Click to expand...
I have long covid mecfs and my feet and legs turn blue. This started only a few weeks after whatever my extreme initial event/trigger was that occurred 7 weeks after a covid infection.
 
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