Abstract DP199: Rapid vascular glycocalyx loss and complement activation drive blood-brain barrier disruption in hyperglycemic stroke

Introduction: Acute hyperglycemia affects ~40% of stroke patients and worsens outcomes despite standard glucose control, yet no targeted therapy exists. We identify a previously unrecognized Metabolic–Complement–Vascular (MCV) axis, where hyperglycemia rapidly disrupts the endothelial glycocalyx and activates vascular complement within hours of stroke onset, defining a new, time-sensitive therapeutic target. Method: Male C57BL/6 mice (10-11 weeks) underwent 30 min transient MCAO with reperfusion to mimic thrombectomy. Hyperglycemia was induced by intraperitoneal glucose injection 10 min before occlusion. BBB disruption was assessed at multiple time points by Evans blue or IgM/IgG staining; neurological deficits, motor function (open field), and mortality were recorded. Glycocalyx disruption was measured by electron microscopy and IB4 staining; complement activation assessed by C3d immunostaining. The role of complement C3 was tested using C3 knockout mice and targeted inhibitor CR2-Crry. Human post-mortem ischemic stroke and control brain tissues (n = 5/group) were analyzed for glycocalyx integrity (UEA I lectin) and vascular immune injury (C3d/IgG). Pre-thrombectomy plasma complement markers (n=66) were analyzed via elastic net regression to predict outcomes. Result: Hyperglycemia caused rapid and severe luminal vascular injury within 4.5 h of stroke, with glycocalyx loss, luminal IgM/IgG deposition, vascular C3 activation, and BBB leakage (n=5, p<0.0001); not observed in normoglycemic stroke. Complement activation persisted after glucose normalization, was exacerbated by reperfusion, and propagated into the brain. This early vascular damage increased mortality (100% vs. 25%, p=0.0008) and worsened neurological deficits (p<0.001). C3 knockout mice had reduced BBB leakage (n=6, p<0.01) and improved function (p<0.01). Targeted C3 inhibition with CR2-Crry at 30 min post-reperfusion preserved BBB integrity and improved function (n=4, p<0.01), providing proof-of-concept for adjunct complement-targeted therapy. In human stroke brain, C3 activation colocalized with luminal glycocalyx loss. In human pre-thrombectomy plasma circulating complement activation markers (Ba, Bb, C4a, C3a) independently predicted modified Rankin Scale outcomes at discharge. Conclusion: These findings reframe acute hyperglycemic stroke as a rapid luminal vascular disorder and identify complement inhibition as a promising adjunct to reperfusion therapy.