Upregulation of AQP4 Improves Blood–Brain Barrier Integrity and Perihematomal Edema Following Intracerebral Hemorrhage

Abstract

In intracerebral hemorrhage (ICH), delayed secondary neural damages largely occur from perihematomal edema (PHE) resulting from the disruption of the blood-brain barrier (BBB). PHE is often considered the principal cause of morbidity and mortality in patients with ICH. Nevertheless, the main cellular mechanism as well as the specific BBB component involved in the formation of PHE after ICH remains elusive. Herein, we evaluated the role of AQP4, a water channel expressed on the astrocytes of the BBB, in the formation of PHE in ICH. The static and dynamic functions of the BBB were evaluated by analyzing the microstructure and leakage assay. Protein changes in the PHE lesion were analyzed and the control mechanism of AQP4 expression by reactive oxygen species was also investigated. Delayed PHE formation due to BBB disruption after ICH was confirmed by the decreased coverage of multiple BBB components and increased dynamic leakages. Microstructure assay showed that among the BBB components, AQP4 showed a markedly decreased expression in the PHE lesions. The decrease in AQP4 was due to microenvironmental ROS derived from the hemorrhage and was restored by treatment with ROS scavenger. AQP4-deficient mice had significantly larger PHE lesions and unfavorable survival outcomes compared with wild-type mice. Our data identify AQP4 as a specific BBB-modulating target for alleviating PHE in ICH. Further comprehensive studies are needed to form the preclinical basis for the use of AQP4 enhancers as BBB modulators for preventing delayed cerebral edema after ICH.

Aquaporin 4 Depolarization-Enhanced Transferrin Infiltration Leads to Neuronal Ferroptosis after Subarachnoid Hemorrhage in Mice

“…AQP4 dysfunction in mouse brain tissue leads to impaired water and solute processing and may lead to brain edema or abnormal protein accumulation [ 60 , 61 ]. Although some studies have shown that AQP4 is involved in brain edema after SAH [ 62 ], in recent years, AQP4 knockout has been found to aggravate brain injury after SAH [ 23 ], suggesting the functional diversity and potential neuroprotective effect of AQP4. Our work is the first to show that AQP4 overexpression can reduce SAH-induced AQP4 depolarization, brain parenchymal ferritin content, and neuronal ferroptosis to a certain extent.…”

“…In addition, it has been shown that SAH impairs the polarization of astrocyte AQP4 [ 21 ], while AQP4 knockout aggravates SAH-induced brain injury through impairment of the glymphoid system [ 22 ]. In addition, literature studies have shown that upregulation of AQP4 improves blood–brain barrier integrity and perihematomal edema following intracerebral hemorrhage [ 23 ].…”

Blood–Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders

“…In support of this hypothesis, a recent publication has explored the upregulation of AQP4 in a double knock-down mouse model with promising results when rescuing the channel activity by an enhancer. The authors suggest a pivotal role of AQP4 in suppressing oedema formation by maintaining BBB integrity and upregulating TJs [ 141 ].…”

Roles of Micro Ribonucleic Acids in Astrocytes After Cerebral Stroke

“…Recent in vivo research shows that AQP4 expression is reduced around the perihematomal edema (PHE) area after intracerebral hemorrhage. The PHE lesions in AQP4-deficient mice were significantly larger than that in the wild-type mice, which is related to poor survival outcomes ( Jeon et al, 2021 ). This result implies that AQP4 occupies a very important position in the occurrence of cerebral edema ( Nagelhus and Ottersen, 2013 ; Zhang J. et al, 2019 ; Chen et al, 2021 ).…”