Endothelial IRS-1 aggravates neurovascular damage after neonatal hypoxic-ischemic brain injury through increasing neuroinflammation

Abstract

Perinatal hypoxic-ischemia (HI) is a major cause of neonatal mortality and long-term neurological morbidity among survivors HI injury not only causes neuron death but also damages endothelial cells within neurovascular unit Maintaining the integrity of whole neurovascular unit is required for proper brain function Disruption of neurovascular unit especially cerebral microvascular endothelial cells leads to BBB perturbation and causes vasogenic cerebral edema and secondary neuronal damage which eventually exacerbates long-term disability Thus there is a new idea to develop means to protect the vasculature to improve HI outcome Our previous study found that dietary restriction (DR) reduced neurovascular damage after HI and conferred long-term protection in the neonatal brain through insulin receptor substrate-1 (IRS-1)-Akt pathway Moreover IRS-1 over-expression protected against oxygen-glucose deprivation (OGD) cell death mainly in the endothelial cells Therefore an endothelium specific IRS-1 transgenic rat was created to delineate the role of IRS-1 in vascular endothelial cells against HI in the neonatal brain We found that over-expressed IRS-1 in the vascular endothelial cells worsened the HI infarct volume with decreased tight junction proteins expression and increased matrix metalloprotein 9 (MMP 9) production and BBB damage Since upregulating adhesion molecules of endothelium increases peripheral leukocytes infiltration in to the damaged brain tissue and subsequently worsen the brain injury we further investigated the expression of adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in our transgenic rats We found endothelial IRS-1 transgenic pups had upregulated VCAM-1 expression as early as 3 hours and ICAM-1 expression at 24 hours after HI It associated with significantly increased microglia activation and neutrophils infiltration at 24 hours after HI The in vitro experiments confirmed that IRS-1 over-expression in human brain microvascular endothelial cells could increase VCAM-1 and ICAM-1 expression before and after oxygen-glucose deprivation (OGD) Blockage of VCAM-1 and ICAM-1 using anti-VCAM-1 and anti-ICAM-1 antibody in our transgenic rats decreased neuronal apoptosis and attenuated MMP 9 production microglia activation and neutrophils infiltration after HI In conclusion IRS-1 specific over-expression in the vascular endothelial cells enhanced VCAM-1 and ICMA-1 expression and exaggerated neuroinflammation and neurovascular damage after HI in the neonatal brain

Date of Award	2015 Sept 4
Original language	English
Supervisor	Yi-Fang Tu (Supervisor)