Endothelin-1 over-expression leads to blood-brain barrier disruption resulting in increased infarct and edema after focal ischemia

Abstract

Induced endothelin-1 (ET-1) expression was observed in astrocytes after experimental ischemic stroke, suggesting a potential role of astrocytic ET-1 in ischemic brain injury. Previously, we showed that transgenic mice over-expressing ET-1 in astrocytes (GET mice) displayed increased cerebral infarct size and more severe neurological deficits upon focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Here, the expression profile of the endothelin system was examined in GET mouse brains after MCAO. Quantitative real-time PCR analyses showed that ET-1 mRNA levels in GET ipsilateral mouse brain after MCAO was further increased, while ET-3 levels stayed relatively constant when compared with sham-operated animals. There was an up-regulation of ETA receptor mRNA levels in GET ipsilateral brains while ETB receptor mRNA levels remained unchanged. In addition, Evans blue extravasation studies showed increased blood–brain barrier (BBB) breakdown in GET mice after MCAO, correlating with our findings that GET mice displayed increased brain swelling and brain water content. Moreover, linear regression analysis showed that severity of infarction and brain swelling correlated with the exacerbation of neurologic deficits. These results suggested that increased astrocytic ET-1 resulted in more BBB disruption leading to increased formation of brain edema, infarct and neurologic deficits after focal cerebral ischemia.