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

• Published in: PloS one 2019-06, Vol.14 (6), p.e0218415-e0218415
• Main Authors: Zhang, Yifan, Xu, Kui, Liu, Yuchi, Erokwu, Bernadette O, Zhao, Pan, Flask, Chris A, Ramos-Estebanez, Ciro, Farr, George W, LaManna, Joseph C, Boron, Walter F, Yu, Xin
• Format: Article
• Language: English
• Subjects: Animals; Aquaporin 4; Aquaporin 4 - genetics; Aquaporins; Astrocytes - metabolism; Astrocytes - pathology; Biological Transport - genetics; Biology and Life Sciences; Biomedical engineering; Biophysics; Blood flow; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain; Brain - blood supply; Brain - metabolism; Brain - pathology; Brain Edema - genetics; Brain Edema - metabolism; Brain Edema - physiopathology; Brain research; Cerebral blood flow; Cerebral edema; Cerebrospinal fluid; Computer and Information Sciences; Cortex; Density; Diagnostic imaging; Drug delivery systems; Edema; Engineering; Exchanging; Glucose; Glucose transporter; Health aspects; Immunohistochemistry; Intoxication; Intravenous administration; Ischemia; Laboratory rats; Long-term effects; Magnetic resonance; Magnetic Resonance Imaging; Male; Medicine and Health Sciences; Methods; Mice; Mice, Knockout; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Neuroimaging; Neurosciences; NMR; Nuclear magnetic resonance; Oxygen; Permeability; Physical Sciences; Physiology; Reduction; Research and Analysis Methods; Rodents; Spin labeling; Studies; Therapeutic applications; Vascularization; Water; Water - metabolism; Water exchange
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0218415

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.