Mechanical thrombectomy has demonstrated clinical benefit in acute ischemic stroke caused by anterior-circulation large-vessel occlusion, but several biological levels can remain separated. Reopening the parent artery is not identical to angiographic reperfusion, adequate tissue-level perfusion, restored microvascular flow, preserved oxygen delivery or neurological recovery. After recanalization, downstream vessels may remain hypoperfused, exhibit uneven capillary flow or shunting, become hyperperfused through failed autoregulation, leak across the blood–brain barrier, or be compressed by edema. The review therefore treats incomplete tissue-level reperfusion as an intermediate imaging and tissue phenotype between technical success and clinical outcome. It emphasizes that temporally aligned measurements are needed to test whether particular biological processes precede or accompany the observed perfusion abnormalities.

The endothelial glycocalyx occupies the luminal surface of blood vessels and includes glycosaminoglycans, membrane-bound proteoglycans, glycoproteins and associated plasma proteins. Its composition and thickness vary by vascular bed, flow state, inflammation, age and disease context. In the brain, it operates within the specialized blood–brain barrier and neurovascular unit, alongside endothelial cells, pericytes, basement membrane, astrocytic endfeet, microglia, neurons and extracellular matrix. The glycocalyx is related to, but not synonymous with, either the blood–brain barrier or the neurovascular unit. An intact layer can limit direct contact between circulating cells and the endothelial membrane, support antithrombotic and anticoagulant surface properties, regulate permeability and participate in shear-dependent nitric-oxide signaling. Experimental cerebral ischemia work links glycocalyx integrity to suppression of endothelial transcytosis and preservation of barrier function, while brain-aging research links glycocalyx dysregulation and mucin-domain glycoproteins to blood–brain barrier stability. These findings strengthen the anatomical rationale for examining the layer after thrombectomy but do not establish that its disruption causes human post-thrombectomy no-reflow.

The proposed two-stage model begins with reduced endothelial-surface resilience. In this review, cardiometabolic vulnerability is a conceptual host context rather than a diagnosis: chronic metabolic, inflammatory, renal and vascular stress may reduce baseline resilience before the ischemic event. Cross-disease vascular evidence associates diabetes and hyperglycemia with oxidative and inflammatory stress and impaired nitric-oxide availability, and hypertension and dyslipidemia with altered mechanotransduction, abnormal hemodynamic stress and inflammatory activation. Renal dysfunction may influence systemic endothelial homeostasis, inflammation and clearance of circulating glycocalyx-related biomarkers, but that relationship has not been validated as a cerebral post-thrombectomy mechanism. Experimental and translational brain evidence also supports aging-related alterations in glycocalyx-associated barrier biology. Indirect clinical studies link cardiometabolic risk states to unfavorable outcomes after endovascular therapy, although they do not identify glycocalyx injury as the operating pathway. The two-stage hypothesis therefore proposes that pre-existing vulnerability may lower the capacity to withstand ischemic and reperfusion-related stress, while acute occlusion adds endothelial hypoxia, ATP depletion, acidosis, ionic dysregulation, low shear and inflammatory signaling before the artery is reopened.

Several acute triggers could converge on the vulnerable luminal interface. Restoration of oxygen and substrate produces abrupt shear changes, reactive oxygen species, leukocyte recruitment, thrombin generation and cytokine signaling that may promote enzymatic shedding of glycocalyx components. Complement activation contributes to cerebral ischemia–reperfusion injury in experimental models, while experimental thrombectomy models implicate succinate-associated metabolic injury, but neither process is specific to the glycocalyx. Stent retrievers, aspiration catheters, repeated passes, clot–device interaction and rapid flow restoration can perturb the vessel wall and endothelium; direct visualization of cerebral glycocalyx damage from these devices in patients remains unavailable. Distal clot migration or residual microemboli can also create patchy low-flow territories and sustain thromboinflammation. These processes may occur upstream, downstream, in parallel with or independently of glycocalyx dysfunction, supporting a network model rather than a single linear cascade.

Loss of the glycocalyx’s normal functions could amplify established no-reflow mechanisms. By separating leukocytes from endothelial adhesion platforms, an intact layer discourages rolling, adhesion and capillary stalling. In a mouse recanalization model, neutrophils obstructed a substantial fraction of capillaries after upstream flow was restored, supporting leukocyte plugging as a no-reflow mechanism, but the experiment did not establish glycocalyx shedding as the initiating event in human thrombectomy. Glycocalyx disruption could also expose procoagulant surfaces and reduce local antithrombotic capacity, potentially contributing to platelet adhesion, fibrin deposition and microthrombosis. Primary experimental stroke work has demonstrated capillary fibrin deposition and stacked erythrocytes after recanalization or thrombolysis, supporting a thrombotic component of no-reflow, while the share attributable specifically to cerebral glycocalyx dysfunction remains unknown.

Other proposed interactions involve mechanosensing, barrier stability and capillary-flow distribution. Because glycocalyx-dependent mechanotransduction links shear stress to endothelial nitric-oxide production, surface damage could make endothelial sensing of restored flow more heterogeneous and potentially contribute to vasomotor mismatch or impaired autoregulation. Imaging of cerebrovascular reactivity after successful endovascular treatment supports persistent hemodynamic dysfunction, but it does not identify glycocalyx causality. Experimental stroke studies associate glycocalyx disruption with increased endothelial transcytosis and blood–brain barrier permeability, while human thrombectomy imaging associates barrier disruption or increased permeability with edema, hemorrhagic transformation and adverse tissue states; neither evidence type is glycocalyx-specific. Pericyte-mediated capillary constriction is well supported experimentally after cerebral ischemia, yet direct coupling between glycocalyx injury and pericytes after thrombectomy has not been demonstrated. Theoretical and imaging work also indicates that heterogeneous capillary transit can impair oxygen extraction even when total cerebral blood flow is not uniformly reduced. Patchy adhesion, microthrombosis, vasomotor mismatch and barrier leakage are possible contributors, but perfusion-metabolic validation is required in thrombectomy populations.

Human biomarker studies do not yet resolve these questions. Syndecan-1, heparan sulfate and hyaluronan can be sampled repeatedly and may reflect shedding products from endothelium, but peripheral concentrations are not brain-specific. They can also derive from the lung, kidney, liver, gut, systemic inflammation, clearance and vascular instrumentation. Paired intracranial and peripheral sampling in large-vessel occlusion cohorts has shown spatial and temporal heterogeneity in syndecan-1, indicating that local distal-occlusion signals and peripheral venous concentrations cannot be assumed to be synchronized. Longitudinal endovascular-therapy and thrombectomy cohorts also show that syndecan-1 behavior depends on sampling time and clinical context. A thrombolysis-treated cohort found higher plasma syndecan-1 associated with unfavorable outcome, whereas a mechanical-thrombectomy cohort reported that lower postoperative-day-1 syndecan-1 was associated with worse prognosis. Prospective 2026 measurements before recanalization and at 24 and 48 hours found treatment-group differences across serial assessments but no direct association between syndecan-1 and either the National Institutes of Health Stroke Scale or the modified Rankin Scale. These divergent results show why an isolated circulating concentration cannot be translated directly into “more” or “less” cerebral glycocalyx injury.

Evidence that downstream microcirculation remains therapeutically actionable does not validate a glycocalyx-specific explanation. The phase 2b CHOICE trial suggested a higher frequency of excellent outcome with intra-arterial alteplase after successful thrombectomy, although it was stopped early and requires replication. The PEARL study subsequently reported a higher proportion of 90-day modified Rankin Scale scores of 0–1 with intra-arterial alteplase after successful endovascular reperfusion in selected patients. Phase 1b/2a data on intra-arterial tenecteplase support dose selection and safety for further study but do not establish definitive efficacy. These trials support the therapeutic actionability of the post-endovascular microcirculation; they do not establish glycocalyx repair as the operative mechanism. Strategies directed at oxidative stress, complement activation, metabolic stress, endothelial inflammation, blood–brain barrier dysfunction, edema, glucose control, blood-pressure variability and systemic inflammatory burden may influence the luminal endothelial surface indirectly, but their effects are pleiotropic and cannot be labeled glycocalyx-specific. Sulodexide, heparanase-related strategies, glycosaminoglycan restoration and preservation of hyaluronan or heparan sulfate are conceptually relevant interventions, yet supporting evidence comes mainly from diabetes, sepsis, non-cerebral vascular injury, animal models or endothelial-cell systems. They remain experimental, cross-disease or trial-enabling candidates rather than validated post-thrombectomy treatments.

The authors propose a prospective cohort of adults with anterior-circulation large-vessel occlusion who achieve near-complete or complete angiographic reperfusion after mechanical thrombectomy. Serial blood samples would be collected before treatment, immediately after recanalization, one to six hours later and at 24 hours, with local arterial sampling only where technically and ethically feasible. Biomarker trajectories would be aligned with immediate or early perfusion imaging, blood–brain barrier assessments, 24-hour final infarct volume and infarct growth, edema, hemorrhagic transformation, early neurological status and 90-day functional outcome. Researchers would prespecify an imaging-defined incomplete-reperfusion phenotype, such as abnormal parenchymal contrast-transit delay after final angiographic reperfusion or residual perfusion abnormality one to six hours after thrombectomy, and test a pathway from biomarker dynamics to impaired microvascular reperfusion, tissue-injury expansion and clinical outcome. Cardiometabolic factors would be modeled as confounders and potential effect modifiers, while competing mechanisms such as distal embolization, microthrombosis, pericyte contraction, endothelial swelling, complement activation and inflammation would be examined in parallel.

The review synthesizes targeted English-language literature available through 30 April 2026 from PubMed/MEDLINE, Web of Science, Embase and Google Scholar. Its final set contains 53 publications, including 38 primary clinical, experimental or modeling reports and 15 reviews, meta-analyses or narrative papers. The authors separated direct human thrombectomy evidence from indirect biomarker and imaging studies, experimental cerebral evidence, cross-disease vascular evidence and hypothesis-generating inference. Because this was a narrative review rather than a systematic review or meta-analysis, it did not include a PRISMA workflow, formal risk-of-bias assessment or prospectively retained record-level screening counts. The framework therefore cannot claim systematic completeness or causal certainty. Its near-term value is to specify experiments that could support, refine or reject the hypothesis: serial, compartment-annotated biomarkers, temporally aligned perfusion and barrier imaging, tissue endpoints and explicit modeling of host vulnerability and competing mechanisms. Until direct cerebral imaging and tightly timed human studies establish the sequence of events, glycocalyx dysfunction remains a biologically plausible amplifier and organizing research framework, not an established cause or a ready-made therapeutic target.

Subject of Research: Endothelial glycocalyx dysfunction as a proposed amplifier of microvascular reperfusion failure after mechanical thrombectomy

Article Title: Endothelial glycocalyx dysfunction in the setting of mechanical thrombectomy: a conceptual link between cardiometabolic vulnerability and microvascular reperfusion failure

Article References: Wu, X., Mi, S., Ma, J., Xing, Y., Li, G., Cao, Z., & Xiong, X. (2026). Endothelial glycocalyx dysfunction in the setting of mechanical thrombectomy: a conceptual link between cardiometabolic vulnerability and microvascular reperfusion failure. Frontiers in Neurology, 17, Article 1919445. https://doi.org/10.3389/fneur.2026.1919445

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1919445

Keywords: mechanical thrombectomy, endothelial glycocalyx, microvascular reperfusion, no-reflow, acute ischemic stroke, cardiometabolic vulnerability, syndecan-1, blood–brain barrier, narrative review, Endothelial, glycocalyx, dysfunction