TY - JOUR
T1 - Developmental changes of L-arginine transport at the blood-brain barrier in rats
AU - Tachikawa, Masanori
AU - Hirose, Shirou
AU - Akanuma, Shin ichi
AU - Matsuyama, Ryo
AU - Hosoya, Ken ichi
N1 - Funding Information:
We thank Mr. N. Kitade for technical assistance on integration plot analysis. This study was supported, in part, by the Japan Agency for Medical Research and Development (AMED), Practical Research Project for Rare/Intractable Diseases, and a Grant-in-Aid for Challenging Exploratory Research ( 16K15153 ) from the Japan Society for the Promotion of Science , Japan.
Publisher Copyright:
© 2017 Elsevier Inc.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/5
Y1 - 2018/5
N2 - L-Arginine is required for regulating synapse formation/patterning and angiogenesis in the developing brain. We hypothesized that this requirement would be met by increased transporter-mediated supply across the blood-brain barrier (BBB). Thus, the purpose of this work was to test the idea that elevation of blood-to-brain L-arginine transport across the BBB in the postnatal period coincides with up-regulation of cationic acid transporter 1 (CAT1) expression in developing brain capillaries. We found that the apparent brain-to-plasma concentration ratio (Kp, app) of L-arginine after intravenous administration during the first and second postnatal weeks was 2-fold greater than that at the adult stage. Kp, app of L-serine was also increased at the first postnatal week. In contrast, Kp, app of D-mannitol, a passively BBB-permeable molecule, did not change, indicating that increased transport of L-arginine and L-serine is not due to BBB immaturity. Double immunohistochemical staining of CAT1 and a marker protein, glucose transporter 1, revealed that CAT1 was localized on both luminal and abluminal membranes of brain capillary endothelial cells during the developmental and adult stages. A dramatic increase in CAT1 expression in the brain was seen at postnatal day 7 (P7) and day 14 (P14) and the expression subsequently decreased as the brain matured. In accordance with this, intense immunostaining of CAT1 was observed in brain capillaries at P7 and P14. These findings strongly support our hypothesis and suggest that the supply of blood-born L-arginine to the brain via CAT1 at the BBB plays a key role in meeting the elevated demand for L-arginine in postnatal brain.
AB - L-Arginine is required for regulating synapse formation/patterning and angiogenesis in the developing brain. We hypothesized that this requirement would be met by increased transporter-mediated supply across the blood-brain barrier (BBB). Thus, the purpose of this work was to test the idea that elevation of blood-to-brain L-arginine transport across the BBB in the postnatal period coincides with up-regulation of cationic acid transporter 1 (CAT1) expression in developing brain capillaries. We found that the apparent brain-to-plasma concentration ratio (Kp, app) of L-arginine after intravenous administration during the first and second postnatal weeks was 2-fold greater than that at the adult stage. Kp, app of L-serine was also increased at the first postnatal week. In contrast, Kp, app of D-mannitol, a passively BBB-permeable molecule, did not change, indicating that increased transport of L-arginine and L-serine is not due to BBB immaturity. Double immunohistochemical staining of CAT1 and a marker protein, glucose transporter 1, revealed that CAT1 was localized on both luminal and abluminal membranes of brain capillary endothelial cells during the developmental and adult stages. A dramatic increase in CAT1 expression in the brain was seen at postnatal day 7 (P7) and day 14 (P14) and the expression subsequently decreased as the brain matured. In accordance with this, intense immunostaining of CAT1 was observed in brain capillaries at P7 and P14. These findings strongly support our hypothesis and suggest that the supply of blood-born L-arginine to the brain via CAT1 at the BBB plays a key role in meeting the elevated demand for L-arginine in postnatal brain.
KW - Alanine-serine-cysteine transporter
KW - Blood-brain barrier
KW - Brain
KW - Capillary
KW - Cationic amino acid transporter 1
KW - Development
KW - Endothelial cell
KW - Immunohistochemistry
KW - L-Arginine
KW - L-Serine
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U2 - 10.1016/j.mvr.2017.12.003
DO - 10.1016/j.mvr.2017.12.003
M3 - Article
C2 - 29247719
AN - SCOPUS:85038849271
VL - 117
SP - 16
EP - 21
JO - Microvascular Research
JF - Microvascular Research
SN - 0026-2862
ER -