Increased cerebral vascularization and decreased water exchange across the blood-brain barrier in aquaporin-4 knockout mice

• DOI: 10.1371/journal.pone.0218415
• Publication Date: 2019-06-20T17:37:45Z
• Authors: Yifan Zhang; Kui Xu; Yuchi Liu; Bernadette O. Erokwu; Pan Zhao; Chris A. Flask; Ciro Ramos-Estebanez; George W. Farr; Joseph C. LaManna; Walter F. Boron; Xin Yu
• Keywords: Aquaporin 4; Male; Mice, Knockout; Neovascularization, Pathologic; Science; Q; R; Brain; Water; Biological Transport; Brain Edema; Magnetic Resonance Imaging; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Blood-Brain Barrier; Astrocytes; Medicine; Animals; Research Article

Aquaporin-4 (AQP4) plays an important role in regulating water exchange across the blood-brain barrier (BBB) and brain-cerebrospinal fluid interface. Studies on AQP-4 knockout mice (AQP4-KO) have reported considerable protection from brain edema induced by acute water intoxication and ischemic stroke, identifying AQP4 as a potential target for therapeutic interventions. However, the long-term effects of chronic AQP4 suppression are yet to be elucidated. In the current study, we evaluated the physiological and structural changes in adult AQP4-KO mice using magnetic resonance imaging (MRI) and immunohistochemical analysis. Water exchange across BBB was assessed by tracking an intravenous bolus injection of oxygen-17 (17O) water (H217O) using 17O-MRI. Cerebral blood flow (CBF) was quantified using arterial spin-labeling (ASL) MRI. Capillary density was determined by immunohistochemical staining for glucose transporter-1 (GLUT1). Compared to wildtype control mice, AQP4-KO mice showed a significant reduction in peak and steady-state H217O uptake despite unaltered CBF. Interestingly, a 22% increase in cortical capillary density was observed in AQP4-KO mice. These results suggest that increased cerebral vascularization may be an adaptive response to chronic reduction in water exchange across BBB in AQP4-KO mice.