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

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 72 h 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.