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.