Open AccessIncreased cerebral vascularization and decreased water exchange across the blood-brain barrier in aquaporin-4 knockout mice
Author(s) -
Yifan Zhang,
Kui Xu,
Yu-Chi Liu,
Bernadette O. Erokwu,
Pan Zhao,
Chris A. Flask,
Ciro Ramos-Estébanez,
George W. Farr,
Joseph C. LaManna,
Walter F. Boron,
Xin Yu
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0218415
Subject(s) - aquaporin 4 , blood–brain barrier , cerebral blood flow , glut1 , aquaporin 1 , interstitial fluid , pathology , medicine , cerebral circulation , knockout mouse , cerebrospinal fluid , chemistry , immunohistochemistry , magnetic resonance imaging , anesthesia , central nervous system , glucose transporter , receptor , water channel , mechanical engineering , insulin , engineering , inlet , radiology
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 ( 17 O) water (H 2 17 O) using 17 O-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 H 2 17 O 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.