Endothelial signal-timing breakdown in myalgic encephalomyelitis / chronic fatigue syndrome
Author: Michael Daniels ·
Version: v2.5 ·
Date: January 10th 2026
This document presents an interpretive systems-level framework and mechanistic hypothesis; it is not clinical guidance.
Note on scope and conceptual placement
Relationship to existing ME/CFS models:
This work builds on established vascular and autonomic frameworks, including the unifying hypothesis proposed by Wirth & Scheibenbogen, which frame ME/CFS as a disorder of impaired physiological regulation involving endothelial dysfunction, hypoperfusion, and secondary mitochondrial impairment. The present manuscript does not replace these models, but refines their causal ordering by specifying a downstream activation mechanism for post-exertional malaise (PEM).
Paper 1 (current focus):
This manuscript defines post-exertional malaise as a shear-activated endothelial failure state. Its focus is the execution-level interface at which normal physiological shear stress becomes injurious due to loss of endothelial signal-timing precision. Emphasis is placed on endothelial control-surface stability, nitric oxide timing, and the roles of the glycocalyx and heparan sulfate as downstream shear–timing sub-interfaces.
Paper 2 (in preparation):
A companion manuscript will address upstream conditioning mechanisms that erode control-surface stability prior to execution-layer failure, including immune signal termination defects, endoplasmic reticulum stress, membrane and lipid maintenance pathways (including SMPDL3B-dependent anchoring), and phosphatase-brake–mediated timing dysregulation.
This document should therefore be read as a trigger- and execution-focused extension of existing ME/CFS regulatory models, not as a complete account of upstream disease initiation.
Post-exertional malaise (PEM) is the defining clinical feature of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), yet its trigger remains poorly explained by models focused on exertional load, inflammation, or primary mitochondrial dysfunction. Existing vascular frameworks describe impaired perfusion and acquired mitochondrial dysfunction as downstream consequences of endothelial and autonomic dysregulation, but do not fully account for the delayed, disproportionate, and state-dependent nature of PEM. Here, we propose that PEM arises from a shear-activated failure state, in which normal physiological shear stress becomes injurious due to loss of endothelial signal-timing precision.
In this framework, endothelial dysfunction is not primarily modeled as nitric oxide (NO) depletion or static vasodilatory failure, but as a breakdown in the spatial and temporal coordination of shear sensing, calcium signaling, caveolin-mediated regulation, and NO release at the endothelial control surface. When intact, this control surface—comprising membrane microdomains, caveolae, the glycocalyx, and associated timing machinery—converts mechanical shear into appropriately localized and transient stabilizing signals. When destabilized, NO signaling becomes mistimed or mislocalized, generating heterogeneous microvascular flow and delayed perfusion instability during recovery.
We further argue that endothelial shear interpretation is a conditioned interface, whose stability depends on upstream immune, metabolic, membrane, and glycosylation-related processes. Genetic and systems-level evidence indicates that perturbations across these domains converge on reduced control-surface robustness, lowering tolerance to otherwise normal physiological stressors such as standing, walking, or cognitive effort. Heparan sulfate within the glycocalyx is positioned as a critical shear–timing sub-interface, whose function depends on underlying membrane organization and is secondarily disrupted by control-surface instability.
By locating the PEM trigger at the point where mechanical shear is translated into endothelial signaling, this model bridges upstream vulnerability with downstream vascular, autonomic, and metabolic consequences described in established ME/CFS frameworks. Post-exertional malaise is thus reframed not as a failure of effort tolerance per se, but as a mechanically activated breakdown of endothelial signal timing that precipitates delayed, system-wide dysfunction.
The Wirth–Scheibenbogen hypothesis frames myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) as an acquired disorder of bioenergetic function driven by chronically impaired blood flow, particularly to skeletal muscle and brain (Wirth & Scheibenbogen, 2021). In this model, vascular dysregulation—arising from β2-adrenergic and muscarinic receptor dysfunction, autonomic imbalance, and endothelial abnormalities—leads to repeated episodes of tissue hypoperfusion and relative hypoxia (Wirth & Scheibenbogen, 2021). Over time, impaired oxygen and substrate delivery is proposed to induce secondary mitochondrial dysfunction, manifesting as reduced ATP availability, abnormal lactate handling, acidosis, and exercise intolerance (Wirth & Scheibenbogen, 2021). Within this framework, mitochondrial impairment is not primary, but emerges as a downstream consequence of sustained vascular and autonomic dysregulation.
The present work is fully compatible with—and explicitly downstream-linked to—this model, but addresses a distinct mechanistic question: why otherwise normal physiological stressors such as standing, walking, or cognitive effort reliably trigger delayed symptom exacerbation in ME/CFS, rather than immediate fatigue alone (Wirth & Scheibenbogen, 2021; van Campen et al., 2020). We propose that the critical missing layer is not the existence of hypoperfusion per se, but the mechanical activation mechanism by which tolerable shear stress precipitates endothelial and perfusion instability during recovery.
Specifically, we model post-exertional malaise as a shear-activated failure state arising from loss of endothelial control-surface precision. In this state, the timing, localization, and coordination of nitric oxide (NO) signaling become unstable under mechanical load, even when baseline endothelial function or NO availability appears preserved (Higashi et al., 2014; Tarbell & Cancel, 2016). This framing refines, rather than contradicts, vascular models of ME/CFS: perfusion deficits are understood to arise dynamically from shear-induced signal-timing failure at the endothelial surface, rather than solely from static vasoconstriction or constitutive NO deficiency.
Figure 1 — Positioning within ME/CFS models: where this paper sits
Section 1 · Conceptual positioningFigure 1. Conceptual positioning of the present model within ME/CFS frameworks. Upstream conditioning factors (immune, membrane, and genetic influences; addressed in a companion paper) shape baseline vulnerability, but do not by themselves explain the defining timing characteristics of PEM. This paper focuses on the endothelial control surface as the execution interface that interprets shear and determines signal timing precision. Downstream, the resulting instability can manifest as hypoperfusion, autonomic stress, and metabolic/mitochondrial consequences consistent with established vascular models (e.g., Wirth–Scheibenbogen).
Within this integrated ordering, the Wirth–Scheibenbogen framework describes the downstream physiological consequences of vascular dysfunction—hypoperfusion, autonomic imbalance, metabolic stress, and eventual mitochondrial impairment—while the present paper defines the trigger-level convergence interface that converts upstream vulnerability into post-exertional collapse (Wirth & Scheibenbogen, 2021). This distinction explains why perfusion abnormalities in ME/CFS may be intermittent, load-dependent, and delayed (van Campen et al., 2020), and why interventions that acutely enhance vasodilation or endothelial activation can transiently improve symptoms yet worsen post-exertional outcomes when underlying control-surface stability is not restored (Tarbell & Cancel, 2016; Higashi et al., 2014).
Accordingly, Paper 1 occupies a mid-stream position within a broader mechanistic sequence. It links upstream immune, membrane, and control-layer vulnerabilities (addressed in Paper 2) to the downstream vascular, autonomic, and metabolic consequences articulated by Wirth and Scheibenbogen (Huang et al., 2026; PrecisionLife, 2025). Post-exertional malaise is thus framed not as a failure of effort tolerance per se, but as a mechanically activated breakdown of endothelial flow control that precipitates the hypoperfusion-driven mitochondrial stress described in established vascular models (Wirth & Scheibenbogen, 2021).
Endothelial dysfunction in ME/CFS is frequently described as a state of nitric oxide (NO) depletion or impaired vasodilatory capacity. This framing appears across vascular and autonomic models of the illness and is supported by evidence of reduced endothelial-dependent vasodilation in specific contexts (Wirth & Scheibenbogen, 2021). However, while reductions in NO bioavailability can occur and are incorporated into several established models of ME/CFS, this explanation alone is insufficient to account for the defining characteristics of post-exertional malaise (PEM), particularly its delayed onset, multi-system involvement, and sensitivity to otherwise modest physiological stressors.
In the present framework, endothelial dysfunction is instead modeled as a failure of NO precision rather than a uniform deficit in NO production. Precision failure refers to disruption in the spatial and temporal coordination of NO signaling relative to mechanical shear, calcium influx, and caveolin-mediated regulation at the endothelial surface. This distinction is critical: endothelial signaling may be quantitatively intact or even intermittently elevated, yet functionally ineffective if NO release is mistimed, mislocalized, or poorly constrained with respect to mechanical demand (Higashi et al., 2014; Tarbell & Cancel, 2016).
Under healthy conditions, endothelial NO signaling is tightly regulated. Shear stress is sensed across the glycocalyx and membrane microdomains; calcium activation and caveolin-1–mediated braking are aligned within stable caveolae; and NO release is localized, transient, and appropriately scaled to stabilize microvascular flow (Weinbaum et al., 2007; Del Pozo et al., 2021). This coordination allows shear stress to function as physiological information rather than as a destabilizing input. When the underlying control architecture is intact, endothelial responses remain robust across changes in posture, activity, and metabolic demand.
When this control architecture is destabilized, however, NO signaling loses precision. Release may occur at inappropriate locations, persist beyond physiological windows, or diffuse excessively across the endothelial surface. Importantly, such miscoordination can phenocopy vasoconstriction, impaired perfusion, or endothelial “stiffness” without requiring global NO depletion (Higashi et al., 2014). In this state, normal physiological shear—such as that generated by standing, walking, or cognitive effort—can become injurious, not because it exceeds capacity, but because it is misinterpreted by an unstable signaling system (Tarbell & Cancel, 2016).
Figure 2 — NO precision failure versus NO depletion
Section 2 · Conceptual hingeFigure 2. Comparison of healthy endothelial nitric oxide (NO) signaling precision versus precision failure under identical shear stress. Panel A illustrates intact glycocalyx and caveolar coupling, enabling localized, transient NO release matched to shear. Panel B shows loss of signal coordination, with mistimed and mislocalized NO despite preserved availability, producing flow heterogeneity that phenocopies vasoconstriction without NO depletion.
Modeling endothelial dysfunction as a precision failure resolves several otherwise paradoxical observations in ME/CFS. First, it explains why endothelial and perfusion abnormalities may emerge primarily under load or during recovery, rather than at rest. Second, it accounts for the coexistence of apparently contradictory findings—regional hypoperfusion alongside markers of oxidative or nitrosative stress—by recognizing that poorly timed NO signaling can increase mechanical heterogeneity and focal shear stress rather than uniformly improving flow (Pahakis et al., 2007; Weinbaum et al., 2007). Third, it clarifies why interventions that acutely enhance NO signaling or endothelial activation can transiently improve symptoms yet precipitate delayed worsening when underlying control-surface stability is not restored (Tarbell & Cancel, 2016; Higashi et al., 2014).
Within this framework, post-exertional malaise is not triggered by excessive exertion per se, nor by a simple failure of vasodilation. Instead, PEM arises from a shear-activated breakdown of endothelial signal timing during recovery (Florian et al., 2003; Tarbell & Cancel, 2016). NO precision failure thus sits upstream of the downstream vascular, autonomic, and metabolic consequences described in established endothelial dysfunction models. This reframing is essential for correctly positioning glycocalyx integrity, heparan sulfate patterning, and membrane microdomain stability as coordinated elements of a unified endothelial control surface—one whose failure converts otherwise normal shear forces into a delayed, system-wide stress signal characteristic of PEM.
Endothelial responses to blood flow depend not on a single molecule or receptor, but on an integrated control surface that interprets mechanical shear and converts it into stabilizing biochemical signals. This control surface comprises coordinated structural and signaling elements, including membrane microdomains, caveolae, the endothelial glycocalyx, cytoskeletal coupling, and tightly regulated signal-timing machinery (Weinbaum et al., 2007; Tarbell & Cancel, 2016). Together, these components ensure that shear stress is sensed, averaged, and translated into spatially and temporally appropriate endothelial responses.
Under physiological conditions, shear functions as information rather than stress. Changes in flow velocity, pulsatility, or direction are continuously detected and integrated across the endothelial surface, allowing vessels to adapt dynamically to posture, activity, and metabolic demand (Florian et al., 2003; Tarbell & Cancel, 2016). This adaptive capacity depends critically on the precision of signal interpretation—specifically, the alignment of mechanical inputs with calcium signaling, caveolin-mediated regulation, and nitric oxide (NO) release within stable microdomains (Feron et al., 1998; Weinbaum et al., 2007).
Figure 3 — The endothelial control surface as a shear-timing system
Section 3–4 · Structural anchorFigure 3. The endothelial control surface conceptualized as a shear-timing system. Mechanical flow and shear are filtered by the glycocalyx and its heparan sulfate (HS) components, then integrated by membrane microdomains and caveolae that spatially coordinate calcium signaling, caveolin-mediated regulation, and eNOS localization. SMPDL3B-conditioned membrane stability is positioned as a structural governor of raft and caveolar geometry, determining how reliably shear inputs remain coupled to downstream signaling. The resulting NO output is therefore defined by localization and timing precision rather than by NO quantity alone.
The concept of an endothelial control surface emphasizes coordination rather than capacity. Individual components—such as eNOS activity, calcium availability, or glycocalyx thickness—may appear intact in isolation, yet endothelial function can still fail if their spatial and temporal relationships are disrupted (Higashi et al., 2014; Tarbell & Cancel, 2016). Precision in this context refers to the ability of the endothelial system to localize signaling to the correct regions, constrain responses to appropriate time windows, and terminate signals reliably once mechanical demand has been met.
Membrane microdomains and caveolae play a central role in this process by organizing receptors, ion channels, and signaling enzymes into functionally coherent units. Caveolae, in particular, act as mechanosensitive platforms that coordinate shear detection with downstream signaling and regulatory braking (Del Pozo et al., 2021). When microdomain organization is stable, endothelial responses remain robust even under fluctuating shear conditions.
A key implication of this framework is that endothelial dysfunction need not arise from excessive shear magnitude. Instead, pathology emerges when the interpretation of shear is degraded. In such cases, otherwise normal levels of mechanical input can be misread, leading to inappropriate or poorly coordinated signaling responses (Tarbell & Cancel, 2016). This distinction is essential for understanding why individuals with ME/CFS may experience symptom exacerbation in response to routine activities that do not approach conventional thresholds of cardiovascular or metabolic stress.
When shear interpretation fails, endothelial signaling becomes heterogeneous across the vascular surface. Some regions may over-respond, others under-respond, producing uneven flow regulation and localized mechanical strain (Pahakis et al., 2007). These effects may be subtle or compensated initially, but they increase reliance on downstream precision mechanisms to maintain stability—setting the stage for delayed failure during recovery.
In the present framework, instability of the endothelial control surface is treated as a precondition for post-exertional malaise, not its direct cause. Loss of precision at this interface lowers the tolerance of the system to mechanical variability, making it vulnerable to activation by ordinary physiological shear (Huang et al., 2026). This instability may arise from multiple upstream influences—including immune signaling, metabolic stress, membrane organization, or impaired repair mechanisms—which are addressed separately in Paper 2.
By defining the endothelial control surface as the locus where mechanical inputs are interpreted, this section establishes the structural and functional context for subsequent sections. The following sections will examine how specific components of this control surface—particularly the glycocalyx and heparan sulfate patterning—contribute to shear–signal timing, and how their dysfunction amplifies the risk of shear-activated endothelial failure and delayed symptom emergence (Florian et al., 2003; Weinbaum et al., 2007).
The endothelial control surface interprets shear stress through a coordinated set of structural and signaling interfaces rather than through a single mechanosensor. Within this system, the endothelial glycocalyx and its heparan sulfate (HS) components function as shear–timing sub-interfaces, while membrane microdomain stability determines whether their signals are integrated coherently (Weinbaum et al., 2007; Tarbell & Cancel, 2016). SMPDL3B occupies a critical upstream position in this architecture by stabilizing lipid rafts and caveolar geometry, thereby conditioning the physical environment in which shear interpretation occurs (Rostami-Afshari et al., 2025).
The endothelial glycocalyx is a dynamic, carbohydrate-rich surface layer lining the luminal face of blood vessels. Rather than acting as a passive barrier, it functions as a mechanical signal filter, averaging shear forces across neighboring regions and constraining mechanotransduction to appropriate spatial and temporal scales (Weinbaum et al., 2007; Tarbell & Cancel, 2016). Through coupling to membrane microdomains, cytoskeletal elements, and signaling complexes, the glycocalyx enables shear stress to be translated into precisely timed and localized biochemical signals, including nitric oxide (NO) release (Pahakis et al., 2007).
Glycocalyx integrity refers not merely to its presence or thickness, but to the coherence of its structure, composition, and surface patterning. When intact, the glycocalyx dampens rapid shear fluctuations and distributes mechanical inputs evenly across the endothelial surface. This buffering function reduces reliance on downstream precision mechanisms and allows endothelial responses to remain stable during changes in posture, activity, thermoregulation, or cognitive demand (Weinbaum et al., 2007).
Disruption of glycocalyx integrity—through thinning, patchiness, altered sulfation, or impaired repair—degrades this filtering capacity (Reitsma et al., 2007). Rather than producing uniform endothelial dysfunction, such disruption generates heterogeneous mechanosignaling, with focal regions of exaggerated strain adjacent to relatively insensitive areas. These conditions place increased demand on membrane microdomains and caveolae to maintain signal coordination, increasing vulnerability to failure under load.
Within the glycocalyx, HS proteoglycans occupy a uniquely important position at the interface between mechanical shear sensing and signal timing. HS chains actively participate in translating shear forces into spatially and temporally precise endothelial signaling through their surface distribution, sulfation patterning, and coupling to membrane microdomains (Florian et al., 2003; Xu & Esko, 2014). In this role, HS contributes to aligning mechanotransduction with downstream events such as calcium influx and NO release (Pahakis et al., 2007).
Crucially, HS does not operate independently. Its function depends on the integrity of the underlying membrane control surface, including lipid rafts, caveolae, and associated signaling scaffolds. In the present framework, HS dysfunction in ME/CFS is therefore modeled as a secondary consequence of membrane instability, rather than as a primary glycocalyx defect (Huang et al., 2026; PrecisionLife, 2025). When membrane organization is compromised, the mechanical and signaling environment in which HS operates is altered, changing how shear forces are perceived, distributed, and translated into endothelial responses.
Under such conditions, HS becomes patchy or functionally mispatterned even in the absence of wholesale glycocalyx loss. Instead of averaging shear across neighboring regions, HS transmits uneven mechanical signals downstream, producing spatially heterogeneous mechanotransduction that challenges downstream signal-timing precision (Florian et al., 2003).
SMPDL3B plays a central role in maintaining lipid-raft stability and caveolar architecture, thereby preserving the physical organization of the endothelial control surface (Rostami-Afshari et al., 2025). When SMPDL3B-dependent membrane organization is intact, caveolae geometry remains stable, receptor microdomains retain spatial coherence, and mechanosensory inputs are integrated across a coordinated surface. This structural stability allows shear signals filtered by the glycocalyx and HS to be interpreted consistently and coupled appropriately to downstream signaling.
When SMPDL3B function is compromised, membrane microdomains lose coherence and caveolar geometry becomes distorted. This destabilization has two critical consequences for shear interpretation. First, mechanical strain imposed by flowing blood is no longer evenly distributed across the endothelial surface, increasing localized stress on glycocalyx and HS components. Second, the altered membrane environment disrupts HS surface residency and sulfation patterning, impairing its ability to function as a reliable shear–timing interface (Del Pozo et al., 2021; Xu & Esko, 2014).
Through these mechanisms, SMPDL3B acts as a structural governor of shear tolerance. Its destabilization does not directly initiate endothelial signaling abnormalities, but lowers the margin within which shear inputs can be interpreted without error. As a result, otherwise normal physiological shear becomes more likely to trigger signal-timing failure.
Effective endothelial NO signaling depends not on enzyme availability alone, but on precise spatial coupling between shear sensing, calcium activation, and caveolin-mediated regulation within intact microdomains (Feron et al., 1998). Glycocalyx disruption, HS mispatterning, and membrane instability together degrade this coupling. When shear inputs are unevenly transmitted and membrane scaffolding is unstable, calcium influx and caveolin-1–mediated braking no longer align reliably with endothelial nitric oxide synthase (eNOS) localization.
The result is NO release that is mistimed, mislocalized, or excessively diffuse, rather than appropriately constrained to regions of physiological demand (Pahakis et al., 2007; Higashi et al., 2014). Importantly, this failure mode does not require reduced NO synthesis. Instead, endothelial dysfunction emerges from breakdown of signal coordination, whereby NO is released at the wrong place or time relative to mechanical load. Such miscoordination increases microvascular flow heterogeneity, amplifies local shear gradients, and promotes delayed perfusion instability during recovery.
In this framework, neither glycocalyx disruption nor HS dysfunction nor SMPDL3B instability is treated as an initiating lesion. Instead, they function as amplifiers of shear-activated endothelial failure. Membrane control-surface instability lowers tolerance to mechanical stress; impaired glycocalyx filtering and HS patterning magnify this vulnerability by degrading shear-signal fidelity. Together, these effects convert otherwise normal physiological shear into a destabilizing input during transitions such as postural change, exertion, or post-exertional recovery.
This ordering resolves a key conceptual tension: glycocalyx and HS abnormalities can be mechanistically central to PEM triggering without being causative of ME/CFS itself. They sit at the execution interface where upstream vulnerabilities converge and downstream signaling fails. Loss of control-surface precision at this interface enables shear stress to act as an activating signal, setting the stage for the delayed, system-wide manifestations of post-exertional malaise.
The preceding sections define the endothelial control surface as a precision system that interprets mechanical shear through coordinated interactions between membrane microdomains, caveolae, the glycocalyx, heparan sulfate (HS) patterning, and nitric oxide (NO) signal timing. When intact, this system allows shear stress to function as stabilizing physiological information. When destabilized, however, the same mechanical inputs can act as activating signals, precipitating delayed endothelial and perfusion instability. Post-exertional malaise emerges at this convergence point (Tarbell & Cancel, 2016; Weinbaum et al., 2007).
Figure 4 — Shear-activated failure state and delayed PEM
Section 5 · Delay mechanismFigure 4. Timeline schematic showing how normal physiological shear can trigger delayed post-exertional malaise (PEM) when the endothelial control surface loses signal-timing precision. Following exertion or postural change, shear input remains within physiologic range, but control surface misinterpretation produces a compensation window in which activity may feel tolerable. During recovery, signal-timing errors accumulate (failure to localize and terminate signaling), leading to delayed endothelial instability and subsequent PEM. Downstream effects (ischemia and ROS) can create self-feeding stress loops that further increase load on endothelial timing precision, reinforcing control-surface misinterpretation.
In this framework, shear stress is not inherently pathological. Under normal conditions, physiological shear generated by standing, walking, or moderate exertion is continuously absorbed and integrated by the endothelial control surface. Pathology arises when the interpretation of shear fails, not when shear magnitude exceeds physiological limits. This distinction explains why individuals with ME/CFS often tolerate brief activity yet develop delayed symptom exacerbation during recovery (van Campen et al., 2020; Wirth & Scheibenbogen, 2021).
Control-surface instability lowers the margin within which shear can be accurately interpreted. Membrane microdomain disorganization, impaired glycocalyx filtering, HS mispatterning, and NO precision failure together reduce the system’s ability to average and terminate mechanosignals. As a result, ordinary shear transitions—particularly those occurring during postural change, exertion, or post-exertional recovery—can initiate maladaptive signaling cascades (Florian et al., 2003; Tarbell & Cancel, 2016).
A defining feature of PEM is its delay. This temporal separation between exertion and symptom emergence is difficult to reconcile with models based solely on immediate energy depletion or static vascular insufficiency. In the present model, delay arises naturally from signal-timing failure at the endothelial surface.
When shear inputs are unevenly transmitted and NO signaling is mistimed or mislocalized, microvascular flow regulation becomes heterogeneous. Some regions experience excessive dilation or prolonged NO exposure, while others remain under-perfused. These discrepancies may initially be compensated, but they impose cumulative mechanical and metabolic strain during recovery. As compensatory capacity is exhausted, endothelial instability propagates downstream, manifesting as delayed hypoperfusion, autonomic imbalance, and metabolic stress (Higashi et al., 2014; Pahakis et al., 2007).
Once shear-activated failure is initiated at the endothelial surface, downstream effects follow the pathways described in established ME/CFS vascular models. Heterogeneous perfusion promotes relative tissue hypoxia, impaired substrate delivery, and metabolic stress, particularly in skeletal muscle and brain. Autonomic reflexes may further amplify instability by altering vascular tone and heart rate in an attempt to restore flow (Wirth & Scheibenbogen, 2021; van Campen et al., 2020).
Within this ordering, mitochondrial dysfunction emerges as a secondary consequence of repeated perfusion instability rather than as a primary defect. This positioning aligns directly with the Wirth–Scheibenbogen hypothesis, which describes acquired mitochondrial dysfunction resulting from chronic or recurrent hypoperfusion. The present paper therefore clarifies how such perfusion instability is episodically triggered, rather than disputing its downstream role (Wirth & Scheibenbogen, 2021).
The shear-activated convergence model also explains why interventions that acutely enhance endothelial activation, vasodilation, or NO signaling may produce transient symptomatic improvement yet worsen post-exertional outcomes. When underlying control-surface precision is compromised, increasing signaling gain without restoring coordination can temporarily mask instability while increasing delayed mechanical and metabolic stress (Tarbell & Cancel, 2016; Higashi et al., 2014).
This phenomenon—often reported clinically as “false energy” or short-lived improvement followed by disproportionate crash—is predicted by a system in which control precision, rather than absolute capacity, is the limiting factor. Restoration of tolerance therefore requires stabilization of the endothelial control surface, not merely augmentation of downstream signaling.
Taken together, these mechanisms support a unified interpretation of post-exertional malaise as a mechanically activated failure state. PEM is not caused by exertion itself, nor by isolated defects in mitochondria, NO production, or vascular tone. Instead, it arises when normal physiological shear interacts with a destabilized endothelial control surface, triggering signal-timing failure that propagates downstream into delayed, system-wide dysfunction.
This convergence point explains the characteristic features of PEM: delay, disproportionate severity, multi-system involvement, and sensitivity to modest stressors. It also establishes a coherent bridge between upstream conditioning factors (addressed in Paper 2) and downstream vascular and metabolic consequences described in existing ME/CFS models (Wirth & Scheibenbogen, 2021; Huang et al., 2026).
The shear-activated failure state described in this paper does not arise in isolation. Rather, it reflects the interaction between normal physiological mechanical inputs and a pre-conditioned endothelial control surface whose stability has been eroded by upstream biological influences. Genetic and systems-level evidence indicates that vulnerability in ME/CFS is distributed across multiple domains that collectively determine the robustness, repair capacity, and signal-termination fidelity of endothelial structures (Huang et al., 2026; PrecisionLife, 2025). These upstream factors do not directly generate post-exertional malaise, but they lower the tolerance of the system to shear, increasing the likelihood that ordinary physiological stressors will activate control-surface failure.
Large-scale genetic analyses in ME/CFS consistently implicate pathways involved in immune regulation, endoplasmic reticulum (ER) stress handling, lipid and membrane metabolism, and glycosylation-related processes (Huang et al., 2026; PrecisionLife, 2025). Importantly, these findings do not converge on genes encoding core endothelial signaling molecules or vasodilatory enzymes themselves. Instead, they point to processes that condition membrane organization, protein folding, signal termination, and surface patterning—all of which are essential for maintaining endothelial control-surface precision under load.
This pattern supports a model in which ME/CFS risk reflects erosion of regulatory and structural buffering capacity, rather than constitutive hyperactivation or deficiency within a single pathway. Such distributed vulnerability explains why baseline measurements may appear normal, yet system stability collapses under dynamic conditions such as exertion or recovery.
Many implicated genetic domains relate directly to membrane composition, lipid handling, and microdomain organization (Huang et al., 2026). These processes influence the stability of lipid rafts and caveolae, which in turn determine how mechanosensory inputs are organized and terminated at the endothelial surface (Del Pozo et al., 2021). Compromised membrane maintenance reduces the precision with which shear signals are localized and increases susceptibility to spatial and temporal signal spillover.
Similarly, genes involved in ER stress resolution and protein quality control shape the recovery and turnover of surface receptors, scaffolding proteins, and glycosylated structures (Huang et al., 2026). Impaired resolution of ER stress can prolong signaling states, interfere with proper membrane repair, and reduce the system’s ability to re-establish baseline control following load. These effects are subtle at rest, but become consequential when mechanical demands fluctuate.
Genetic signals related to glycosylation pathways further support the concept of a conditioned shear interface (PrecisionLife, 2025; Xu & Esko, 2014). Glycosylation determines not only the presence but the patterning, spacing, and turnover of surface molecules within the glycocalyx, including heparan sulfate proteoglycans. Altered glycosylation does not directly cause endothelial dysfunction, but it degrades the fidelity with which shear forces are filtered and averaged across the endothelial surface.
When combined with membrane instability and impaired signal termination, such alterations increase mechanical heterogeneity and raise reliance on downstream precision mechanisms to maintain flow stability. In this context, glycocalyx and HS abnormalities function as amplifiers of vulnerability, not primary lesions.
Within the structure of this paper series, genetic evidence is used here to define the vulnerability landscape, not to specify mechanistic causation. These findings explain why endothelial control-surface instability is plausible, persistent, and heterogeneously expressed across individuals with ME/CFS. They also clarify why no single biomarker or pathway is sufficient to capture disease risk or severity (Huang et al., 2026; PrecisionLife, 2025).
Detailed mechanistic interpretation of these genetic domains—including their roles in immune signal termination, ER stress recovery, lipid trafficking, and membrane repair—is addressed in Paper 2. In the present paper, their relevance lies in demonstrating that shear-activated endothelial failure emerges from a conditioned system, in which upstream control-layer erosion lowers the threshold for mechanically triggered collapse.
This paper reframes post-exertional malaise (PEM) as a shear-activated failure state arising from loss of endothelial signal-timing precision, rather than as a direct consequence of exertional overload, static vascular insufficiency, or primary mitochondrial dysfunction. By locating the PEM trigger at the endothelial control surface—where mechanical shear is interpreted and translated into biochemical signals—we provide a mechanistic explanation for the delayed, disproportionate, and multi-system nature of symptom exacerbation in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) (Wirth & Scheibenbogen, 2021; Tarbell & Cancel, 2016).
Several persistent paradoxes in ME/CFS are naturally resolved within this framework. First, the delay between exertion and symptom onset follows directly from signal-timing failure rather than immediate energetic depletion. Control-surface instability allows compensatory mechanisms to temporarily maintain function despite miscoordination, with collapse occurring during recovery as cumulative mechanical and metabolic strain exceeds regulatory capacity (Higashi et al., 2014).
Second, the model explains why individuals with ME/CFS may tolerate brief activity yet deteriorate following otherwise modest stressors. Pathology arises not from shear magnitude but from degraded interpretation of shear. As a result, activities that remain within conventional physiological limits can nonetheless activate failure in a system whose tolerance has been eroded (van Campen et al., 2020).
Third, the coexistence of apparently contradictory findings—regional hypoperfusion alongside markers of oxidative or nitrosative stress—is accounted for by spatially heterogeneous signaling. Mistimed or mislocalized nitric oxide (NO) release increases flow irregularity and focal shear stress rather than uniformly improving perfusion, producing both under-perfused regions and localized biochemical stress (Pahakis et al., 2007; Higashi et al., 2014).
The shear-activated control-surface model is not intended to replace established vascular frameworks of ME/CFS, but to refine their causal ordering. In particular, it is fully compatible with models describing impaired blood flow and acquired mitochondrial dysfunction as downstream consequences of vascular and autonomic dysregulation. By specifying how endothelial signal-timing failure is mechanically activated, the present work clarifies how perfusion instability can be episodic, load-dependent, and delayed—features that are difficult to reconcile with static deficit models alone (Wirth & Scheibenbogen, 2021).
Within this ordering, mitochondrial abnormalities emerge as secondary responses to repeated or prolonged hypoperfusion rather than as initiating lesions. This distinction has important implications for interpretation of metabolic findings and for therapeutic strategies that focus exclusively on energy production without addressing upstream control precision.
A further implication of this framework is its ability to explain paradoxical treatment responses frequently reported in ME/CFS. Interventions that acutely enhance endothelial activation, vasodilation, or NO signaling may transiently improve symptoms by overriding impaired coordination. However, when underlying control-surface stability is not restored, increased signaling gain can exacerbate delayed mechanical and metabolic stress, leading to disproportionate post-exertional worsening (Tarbell & Cancel, 2016; Higashi et al., 2014).
This phenomenon—often described clinically as a short-lived improvement followed by a larger crash—reflects a mismatch between signal amplification and control precision. Effective restoration of tolerance therefore requires stabilization of the endothelial control surface itself, rather than indiscriminate augmentation of downstream signaling pathways.
Genetic and systems-level evidence further supports the interpretation of PEM as an emergent property of a conditioned system. Rather than implicating a single causative pathway, upstream genetic signals map to processes that maintain membrane organization, glycosylation fidelity, immune signal termination, and recovery capacity (Huang et al., 2026; PrecisionLife, 2025). These domains collectively shape the robustness of the endothelial control surface and determine the margin within which mechanical inputs can be safely interpreted.
By integrating this evidence, the present model explains why ME/CFS exhibits heterogeneity in presentation and severity, why baseline measurements may be normal, and why vulnerability is expressed primarily under dynamic conditions. Importantly, genetic predisposition does not directly generate PEM, but lowers the threshold at which shear-activated failure occurs.
The present paper is intentionally scoped to the execution and trigger level of PEM. It does not claim that endothelial control-surface instability is the primary cause of ME/CFS, nor that glycocalyx, heparan sulfate, or membrane proteins represent initiating lesions. Instead, it defines where and how upstream vulnerabilities converge to produce the characteristic post-exertional phenotype.
Detailed mechanistic exploration of upstream conditioning processes—including immune control-layer erosion, endoplasmic reticulum stress, lipid and membrane maintenance, and signal termination failure—is addressed in a companion paper (Paper 2). Together, these works aim to establish a coherent, multi-layered framework that links genetic susceptibility, control-surface instability, and downstream physiological consequences without collapsing causality into a single pathway.
Figure 5 — PEM as a mechanically activated failure state (integrated synthesis)
Discussion / Conclusion · Integrated synthesisFigure 5. One-panel integrated synthesis of PEM as a mechanically activated failure state. Normal physiological shear is not inherently harmful, but interacts with a conditioned endothelial control surface that must interpret shear with high timing precision. When coupling across the control surface is intact, shear is converted into stable flow regulation. When coupling fails, shear can produce precision loss (patchy signaling and mislocalized NO) with heterogeneous microvascular flow, leading to delayed instability during recovery and PEM. Downstream consequences include hypoperfusion, autonomic stress, and metabolic/mitochondrial dysfunction consistent with established vascular frameworks (e.g., Wirth–Scheibenbogen).
This work proposes a mechanistic framework for post-exertional malaise (PEM) in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) centered on shear-activated failure of endothelial signal timing. Several limitations and scope constraints should be noted to ensure appropriate interpretation.
First, the model presented here is conceptual and integrative, rather than a direct test of specific molecular interventions. While it is grounded in existing experimental, clinical, and genetic evidence, it does not assert that any single molecule, receptor, or structural component—such as nitric oxide, heparan sulfate, or SMPDL3B—is independently sufficient to cause ME/CFS or PEM. These elements are treated as components of a coordinated control surface whose stability depends on distributed upstream processes.
Second, this paper does not claim that endothelial control-surface instability represents the primary initiating lesion in ME/CFS. Instead, it defines the execution-level interface at which upstream vulnerabilities converge to produce post-exertional collapse. Immune dysregulation, metabolic stress, membrane maintenance failure, and impaired signal termination are treated as conditioning factors that lower tolerance to mechanical shear, rather than as direct triggers. Detailed analysis of these upstream mechanisms is addressed in a companion paper.
Third, mitochondrial dysfunction is not modeled here as a primary defect. While metabolic abnormalities and impaired energy recovery are central features of ME/CFS, they are interpreted as downstream consequences of repeated or sustained perfusion instability rather than as initiating causes. This ordering is consistent with vascular and autonomic models of the illness and does not exclude additional metabolic contributions in later disease stages.
Fourth, the framework does not imply that all individuals with ME/CFS share identical mechanisms or severity. Genetic, environmental, and physiological heterogeneity is expected to influence the degree of control-surface instability, the threshold for shear-activated failure, and the balance between compensatory and maladaptive responses. As such, the model is intended to explain shared features of PEM, not to reduce the illness to a single pathway or biomarker.
Finally, empirical validation of specific components of this model—such as dynamic measurements of endothelial signal timing, glycocalyx patterning under load, or shear-dependent perfusion heterogeneity—remains an important direction for future research. The present work aims to clarify conceptual structure and causal ordering to guide such investigations, rather than to provide definitive experimental proof.
Post-exertional malaise (PEM) remains the defining and most disabling feature of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), yet its trigger has been difficult to reconcile within models focused solely on exertional load, inflammation, or static vascular and metabolic deficits. In this paper, we have proposed that PEM is best understood as a shear-activated failure state, arising when normal physiological mechanical forces interact with a destabilized endothelial control surface.
By reframing endothelial dysfunction as a failure of signal-timing precision rather than uniform nitric oxide depletion or fixed vasodilatory incapacity, this model explains why symptoms are delayed, disproportionate, and highly sensitive to otherwise modest stressors. The endothelial control surface— comprising membrane microdomains, caveolae, the glycocalyx, and associated timing machinery—emerges as the execution-level interface at which upstream vulnerability converges and downstream dysfunction is initiated.
This framework integrates seamlessly with established vascular and metabolic models of ME/CFS. Impaired perfusion, autonomic dysregulation, and acquired mitochondrial dysfunction are preserved as downstream consequences, while the present work clarifies how and when these processes are episodically activated. Genetic and systems-level evidence further supports the interpretation of PEM as an emergent property of a conditioned system, in which upstream immune, metabolic, membrane, and glycosylation-related perturbations reduce tolerance to mechanical shear without directly generating symptoms at rest.
By locating the PEM trigger at the point where shear is interpreted rather than produced, this model resolves longstanding paradoxes in ME/CFS research and clinical experience, including delayed symptom onset, paradoxical responses to vasodilatory interventions, and the mismatch between baseline measurements and post-exertional collapse. It also highlights the importance of restoring control-surface stability and signal coordination, rather than indiscriminately amplifying downstream pathways.
Together with a companion paper addressing upstream conditioning mechanisms, this work provides a coherent, multi-layered framework linking genetic susceptibility, endothelial control-surface instability, and downstream physiological consequences. Post-exertional malaise is thus reframed not as a failure of effort tolerance, but as a mechanically activated breakdown of endothelial signal timing—an interpretation that offers a unifying lens for future investigation and therapeutic strategy in ME/CFS.
The documents listed below define the conceptual and methodological framework used to interpret genetic signals and physiological mechanisms in this paper. Collectively, they establish layer boundaries, phenotype discipline, and phase dependence within the Gut–Liver–Autonomic (GLA) system architecture.
These materials are provided for transparency and interpretive context only. They are not cited as evidentiary sources and should be read as evolving systems-biology models used to organize and constrain interpretation, rather than as claims of mechanism or causation.
Core GLA framework documents
SMPDL3B phenotype frameworks
Control layers & system modulators