Abstract
Edema is a hallmark of many brain disorders including stroke. During vasogenic edema, blood-brain barrier (BBB) permeability increases, contributing to the entry of plasma proteins followed by water. Caveolae and caveolin-1 (Cav-1) are involved in these BBB permeability changes. The expression of the aquaporin-4 (AQP4) water channel relates to brain swelling, however, its regulation is poorly understood. Here we tested whether Cav-1 regulates AQP4 expression in the perivascular region after brain ischemia in mice. We showed that Cav-1 knockout mice had enhanced hemispheric swelling and decreased perivascular AQP4 expression in perilesional and contralateral cortical regions compared to wild-type. Glial fibrillary acidic protein-positive astrocytes displayed less branching and ramification in Cav-1 knockout mice compared to wild-type animals. There was a positive correlation between the area of perivascular AQP4-immunolabelling and branch length of Glial fibrillary acidic protein-positive astrocytes in wild-type mice, not seen in Cav-1 knockout mice. In summary, we show for the first time that loss of Cav-1 results in decreased AQP4 expression and impaired perivascular AQP4 covering after cerebral ischemia associated with altered reactive astrocyte morphology and enhanced brain swelling. Therapeutic approaches targeting Cav-1 may provide new opportunities for improving stroke outcome.Significance StatementSevere brain edema worsens outcome in stroke patients. Available treatments for stroke-related edema are not efficient and molecular and cellular mechanisms are poorly understood. Cellular water channels, aquaporins (AQPs), are mainly expressed in astrocytes in the brain and play a key role in water movements and cerebral edema, while endothelial caveolins have been suggested to play a role in vasogenic edema. Here we used an integrative approach to study possible interaction between AQP4 and caveolin-1 (Cav-1) after stroke. Absence of Cav-1 was associated with perivascular changes in AQP4 expression and enhanced brain swelling at 3 days after cerebral ischemia. The present work indicates a direct or indirect effect of Cav-1 on perivascular AQP4, which may lead to novel edema therapy.
Highlights
Cerebral edema is a hallmark of many brain diseases including stroke
We investigated if Cav-1 is involved in AQP4 expression and cellular distribution after brain ischemia relating to astrogliosis and brain swelling
Decreased Glial Acidic Fibrillary Protein (GFAP) staining was observed in the ipsilateral striatum of both genotypes after stroke with a larger decrease in Cav-1 KO mice than WT mice at 72 h after stroke onset (Figure 1B)
Summary
Cerebral edema is a hallmark of many brain diseases including stroke. It is characterized by a net increase in water in the brain tissue, triggering tissue swelling. Critical for the BBB function, restricts the passage of molecules from blood to the brain tissue via the presence of tight junctions between endothelial cells and specific transporters (Villabona-Rueda et al, 2019) and a low level of transcytosis (Ayloo and Gu, 2019). The increase in BBB permeability after stroke (Sadeghian et al, 2018) has been linked to an early increase in transcytosis (Knowland et al, 2014), which is caveolae and Cav-1 dependent (Knowland et al, 2014; Sadeghian et al, 2018). Choi and colleagues showed that Cav-1 overexpression attenuated brain edema after cerebral ischemia in the rat (Choi et al, 2016)
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