Luminal Vascular Dysfunction Drives Rapid Blood Brain Barrier Injury in Hyperglycemic Stroke: Key Roles for Luminal...

Area of Science:

• Neuroscience
• Immunology
• Vascular Biology

Background:

• Acute hyperglycemia affects 40% of stroke patients, worsening outcomes.
• Mechanisms linking hyperglycemia to stroke injury and effective therapies remain unclear.

Purpose of the Study:

• To investigate the mechanisms linking acute hyperglycemia to stroke-induced brain injury.
• To evaluate the therapeutic potential of targeting the identified mechanisms.

Main Methods:

• Utilized a mouse model of acute hyperglycemic stroke.
• Assessed blood-brain barrier (BBB) integrity, neurological deficits, and mortality.
• Examined endothelial glycocalyx and complement activation in mouse and human tissues; analyzed plasma complement markers in stroke patients.

Main Results:

• Hyperglycemic stroke mice showed accelerated BBB breakdown, greater deficits, and higher mortality.
• Acute hyperglycemia caused rapid endothelial glycocalyx loss and vascular complement C3 activation, leading to BBB disruption.
• Complement activation was confirmed as causal; inhibition post-reperfusion improved outcomes in mice and plasma markers predicted outcomes in humans.

Conclusions:

• Established a novel Metabolic-Complement-Vascular (MCV) axis linking hyperglycemia to BBB breakdown via glycocalyx loss and complement activation.
• Demonstrated that complement inhibition post-reperfusion is a time-specific, luminal-directed therapeutic strategy for hyperglycemic stroke.
• Identified pre-thrombectomy plasma complement markers as predictors of clinical outcomes, enabling risk stratification and personalized therapy.