Abstract WP492: Differential Effects of Iron Chelation With Deferoxamine on Post-Stroke Neurovascular Inflammation: Disease and Sex Interactions

Abstract

We have shown that 1) poor recovery in diabetes is associated with greater hemorrhagic transformation and significant loss of the cerebrovasculature, and 2) iron chelation therapy with deferoxamine (DFX) improves sensorimotor and cognitive outcomes while preventing vasoregression in male diabetic animals after stroke. This study tested the hypotheses that 1) diabetes mediates pathological post-stroke neovascularization in females and 2) DFX attenuates microglial activation and pathological neurovascular remodeling in both sexes. Control and diabetic animals were subjected to embolic middle cerebral artery occlusion (MCAO). DFX (100 mg/kg) or vehicle was given 1hour after MCAO and repeated every 12h for 7 days after stroke. Functional outcomes were assessed over time. Vascular indices, microglial morphology (activation), and neurovascular integrity (IgG and unpolarized Aquaporin-4) were measured at Day 14. Male and female microvascular endothelial cells (BMVECs) treated with iron and/or DFX were tested for viability and endothelial mesenchymal transition (EndMT) markers. DFX preserved vascular volume post-stroke in diabetic males. Stroke did not cause vasoregression in diabetic female animals; however, DFX reduced vascular indices while improving sensorimotor but not cognitive outcomes in both control and diabetic females. Ischemic injury amplified microglial activation and neurovascular remodeling in diabetes while DFX treatment restored these changes to control levels in male diabetic animals but not in females (Table). Female BMVECs grown under diabetic conditions expressed α-SMA and N-cadherin while VE-cadherin was decreased, indicative of EndMT (p<0.05 vs normal glucose). Data suggest that DFX treatment has sex- and disease-dependent effects on post-stroke neovascularization. Additional studies will aim to address the mechanisms by which DFX exerts these differential effects on functional outcomes and neurovascular remodeling.