Abstract T MP21: Administration Of Atorvastatin During Angiogenesis After Stroke Promotes Long-term Restoration Of BBB In Peri-infarct Regions Of Rat Brains

Abstract

Our previous study shows that the newly formed vessels in peri-infarct regions of ischemic hemispheres have hyperperfusion and high blood-brain barrier (BBB) permeability at 3 weeks after stroke. This is due to lack of tight junction proteins (TJP), occludin and ZO-1, in endothelial cells of the new vessels. We proposed that at this stage pro-angiogenic agents could be used to facilitate restoration of BBB to promote functional neurovascular remodeling in peri-infarct regions. In this study, we investigated the effects of atorvastatin, as a pro-angiogenic agent, on the brain recovery stage after stroke. Adult spontaneously hypertensive rats had a transient middle cerebral artery occlusion (MCAO) with reperfusion. Atorvastatin, at a low dose of 3 mg/kg, was delivered daily starting at 14 days after MCAO for 7 days via gavage. Multimodal MRI and behavioral test were performed at different times up to 8 weeks after MCAO. Animals were sacrificed at 8 weeks for immunohistochemical and biochemical analyses. Multimodal MRI showed that treatment with atorvastatin reduced core-infarct size and restored cerebral blood flow compared with vehicle treated brain. RotoRod tests demonstrated that atorvastatin improves long-term behavioral outcome of the stroke rats. At 8 weeks, treatment with atorvastatin markedly increased expression of occludin and ZO-1 in pericytes and endothelial cells of angiogenic vessels in peri-infarct areas. Importantly, ZO-1, which was found in pericytes surrounding the angiogenic vessels, was seen in the endothelial cell forming continuous-line-like structure in atorvastatin treated brain. Factors associated with angiogenesis, such as VEGF-A, TGF-β1, and Alk-1, were significantly increased in atorvastatin treated group. We also found that atorvastatin significantly increased expression of connexin 43, which forms gap junctions to transfer molecules between cells, in pericytes and astrocytes surrounding the new vessels. Our results indicate that treatment with low-dose atorvastatin during recovery can stabilize the newly formed vessels and facilitate full development of BBB. Pericytes and astrocytes play a key role in determination of functional BBB restoration.