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

## TL;DR

Blocking sVCAM1 and GSK3β in diabetic mice reduces brain swelling and stroke damage by stabilizing blood vessels and lowering histamine.

## Contribution

Identifies two complementary mast cell pathways in T2D and proposes dual targeting of sVCAM1 and GSK3β to protect cerebrovascular function.

## Key findings

- Insulin resistance and sVCAM1 in mast cells increase histamine, causing cerebrovascular dysfunction.
- Dual targeting of sVCAM1 and GSK3β lowers histamine, improves blood-brain barrier integrity, and reduces stroke damage.
- Pharmacological inhibition of GSK3β and sVCAM1 neutralization stabilize mast cells and restore cerebral artery function.

## Abstract

What are the main findings?
Insulin resistance and soluble VCAM1 act through complementary pathways in mast cells to elevate circulating histamine levels, leading to cerebrovascular dysfunction.Dual targeting of sVCAM1 and GSK3β lowered histamine, improved endothelial barrier metrics and cerebral artery tone, and reduced infarct size and edema.

Insulin resistance and soluble VCAM1 act through complementary pathways in mast cells to elevate circulating histamine levels, leading to cerebrovascular dysfunction.

Dual targeting of sVCAM1 and GSK3β lowered histamine, improved endothelial barrier metrics and cerebral artery tone, and reduced infarct size and edema.

What are the implications of the main findings?
Treating diabetic cerebrovascular dysfunction requires pathway-specific interventions beyond glycemic lowering.Blocking sVCAM1 signaling and inhibiting GSK3β represent complementary therapeutic strategies to protect vascular function in the diabetic brain.

Treating diabetic cerebrovascular dysfunction requires pathway-specific interventions beyond glycemic lowering.

Blocking sVCAM1 signaling and inhibiting GSK3β represent complementary therapeutic strategies to protect vascular function in the diabetic brain.

Type 2 diabetes (T2D) features insulin resistance that promotes cerebrovascular injury, yet the immune signals linking metabolic stress to vascular dysfunction remain unclear. We tested the hypothesis that insulin resistance and soluble vascular cell adhesion molecule-1 (sVCAM1) act through complementary pathways in mast cells (MCs) to raise circulating histamine levels and impair cerebral vascular function. In a high-fat diet (HFD) plus low-dose streptozotocin (STZ) model, plasma histamine rose sharply after the onset of insulin resistance and remained elevated. Plasma sVCAM1 levels also increased after insulin resistance. In vitro, recombinant sVCAM1 upregulated histidine decarboxylase (HDC) in native MCs in a dose-dependent manner, indicating a shift toward histamine synthesis, but did not enhance degranulation. In contrast, pharmacological inhibition of Akt with MK2206 activated Glycogen Synthase Kinase 3 beta (GSK3β) and increased MC degranulation without affecting HDC expression. Diabetic endothelial cell monolayers exhibited a ~twofold reduction in transendothelial electrical resistance consistent with impaired blood–brain barrier (BBB) integrity. Diabetic cerebral arteries showed receptor remodeling that favored constriction with histamine H1 receptor (H1R) expression increasing in vascular smooth muscle, while endothelial H1R and histamine H2 receptor (H2R) decreased. Functionally, insulin treatment lowered HOMA2-IR in T2D mice but did not restore cerebral artery myogenic tone or improve stroke outcomes after distal middle cerebral artery occlusion (dMCAO). Neutralizing VCAM1 with a monoclonal antibody reduced circulating sVCAM1 and histamine levels, and, together with the GSK3β inhibitor Tideglusib, stabilized MCs, normalized cerebral artery tone, and reduced post-MCAO infarct size and edema. These findings identify two distinct yet complementary mast cell pathways in T2D, highlight an immune-vascular interface that drives cerebrovascular dysfunction, and propose sVCAM1 blockade plus GSK3β inhibition as rational strategies to protect cerebral vascular function in the diabetic brain.