Relationship Between Hematoma Expansion Induced by Hypertension and Hyperglycemia and Blood-brain Barrier Disruption in Mice and Its Possible Mechanism: Role of Aquaporin-4 and Connexin43.

Abstract

We aimed to select an optimized hematoma expansion (HE) model and investigate the possible mechanism of blood-brain barrier (BBB) damage in mice. The results showed that HE occurred in the group with hypertension combined with hyperglycemia (HH-HE) from 3 to 72h after intracerebral hemorrhage; this was accompanied by neurological deficits and hardly influenced the survival rate. The receiver operating characteristic curve suggested the criterion for this model was hematoma volume expansion ≥ 45.0%. Meanwhile, HH-HE aggravated BBB disruption. A protector of the BBB reduced HH-HE, while a BBB disruptor induced a further HH-HE. Aquaporin-4 (AQP4) knock-out led to larger hematoma volume and more severe BBB disruption. Furthermore, hematoma volume and BBB disruption were reduced by multiple connexin43 (Cx43) inhibitors in the wild-type group but not in the AQP4 knock-out group. In conclusion, the optimized HE model is induced by hypertension and hyperglycemia with the criterion of hematoma volume expanding ≥ 45.0%. HH-HE leads to BBB disruption, which is dependent on AQP4 and Cx43.