Targeting Soluble VCAM1 and GSK3β Improves Cerebrovascular Function and Reduces Stroke Pathology in Diabetic Mice

Area of Science:

• Immunology
• Endocrinology
• Neuroscience

Background:

• Type 2 diabetes (T2D) involves insulin resistance and cerebrovascular injury.
• Immune signals linking metabolic stress to vascular dysfunction in T2D are not fully understood.

Purpose of the Study:

• To investigate if insulin resistance and soluble vascular cell adhesion molecule-1 (sVCAM1) impact mast cells (MCs) to affect histamine levels and cerebral vascular function.
• To explore therapeutic strategies for protecting the diabetic brain.

Main Methods:

• Utilized a high-fat diet (HFD) plus streptozotocin (STZ) mouse model of T2D.
• Assessed plasma histamine, sVCAM1, and MC responses in vitro and in vivo.
• Examined blood-brain barrier (BBB) integrity and cerebral artery remodeling.
• Evaluated the effects of insulin, VCAM1 neutralization, and GSK3β inhibition on cerebrovascular function and stroke outcomes after middle cerebral artery occlusion (MCAO).

Main Results:

• T2D mice showed elevated plasma histamine and sVCAM1, linked to insulin resistance.
• sVCAM1 increased histamine synthesis in MCs, while Akt inhibition promoted MC degranulation.
• Diabetic mice exhibited impaired BBB integrity and cerebral artery constriction.
• VCAM1 blockade and GSK3β inhibition normalized cerebral artery tone and reduced stroke damage.

Conclusions:

• Identified two distinct mast cell pathways in T2D contributing to cerebrovascular dysfunction.
• Demonstrated that sVCAM1 blockade combined with GSK3β inhibition protects cerebral vascular function in T2D.
• Proposed these combined strategies as potential treatments for diabetic cerebrovascular complications.