eNOS Uncoupling, Shear-Stress Tolerance, and the Two-Threshold Model of Post-Exertional Malaise in Long COVID: A...

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.

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.

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.

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.