PMID- 25446323
OWN - NLM
STAT- MEDLINE
DCOM- 20150210
LR  - 20211203
IS  - 1096-0007 (Electronic)
IS  - 0014-4835 (Linking)
VI  - 129
DP  - 2014 Dec
TI  - Effects of mTOR inhibition on normal retinal vascular development in the mouse.
PG  - 127-34
LID - S0014-4835(14)00301-7 [pii]
LID - 10.1016/j.exer.2014.11.005 [doi]
AB  - We aimed to determine the role of age-related changes in the mammalian target of 
      rapamycin (mTOR) activity in endothelial cell growth during retinal vascular 
      development in mice. Mice were administered the mTOR inhibitor rapamycin as 
      follows: (i) for 6 days from postnatal day 0 (P0) to P5, (ii) for 2 days on P6 
      and P7, and (iii) for 2 days on P12 and P13. For comparison, we examined the 
      effects of KRN633, an inhibitor of vascular endothelial growth factor (VEGF) 
      receptor tyrosine kinase, on retinal vascular development. The retinal 
      vasculature and phosphorylated ribosomal protein S6 (pS6), a downstream indicator 
      of mTOR activity, were evaluated using immunohistochemistry. Vascularization was 
      delayed and capillary density was reduced in mice administered rapamycin from P0 
      to P5 compared to the vehicle-treated mice. Rapamycin administration on P6 and P7 
      decreased the vascular density but did not significantly delay the radial 
      vascular growth. Rapamycin administration on P12 and P13 did not significantly 
      affect the retinal superficial blood vessels. Immunoreactivity for pS6 was 
      detected in both endothelial cells in the vascular front and non-vascular cells 
      in the retinal parenchyma, and rapamycin markedly diminished the pS6 
      immunoreactivity. KRN633 administration on P0 and P1 completely inhibited retinal 
      vascularization. The effects of KRN633 on retinal blood vessels decreased in 
      magnitude in an age-dependent manner. These results suggest that the mTOR pathway 
      in endothelial cells activated by VEGF contributes to physiologic vascular 
      development, and that the mTOR pathway in endothelial cells is modulated in a 
      postnatal age-dependent manner.
CI  - Copyright (c) 2014 Elsevier Ltd. All rights reserved.
FAU - Yagasaki, Rina
AU  - Yagasaki R
AD  - Department of Molecular Pharmacology, Kitasato University School of 
      Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
FAU - Nakahara, Tsutomu
AU  - Nakahara T
AD  - Department of Molecular Pharmacology, Kitasato University School of 
      Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. 
      Electronic address: nakaharat@pharm.kitasato-u.ac.jp.
FAU - Mori, Asami
AU  - Mori A
AD  - Department of Molecular Pharmacology, Kitasato University School of 
      Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
FAU - Sakamoto, Kenji
AU  - Sakamoto K
AD  - Department of Molecular Pharmacology, Kitasato University School of 
      Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
FAU - Ishii, Kunio
AU  - Ishii K
AD  - Department of Molecular Pharmacology, Kitasato University School of 
      Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141108
PL  - England
TA  - Exp Eye Res
JT  - Experimental eye research
JID - 0370707
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Quinazolines)
RN  - E1V875I8DX 
      (N-(2-chloro-4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl)-N'-propylurea)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Count
MH  - Cell Growth Processes/drug effects
MH  - Endothelium, Vascular/cytology/drug effects/growth & development
MH  - Female
MH  - Male
MH  - Mice
MH  - Phenylurea Compounds/*pharmacology
MH  - Quinazolines/*pharmacology
MH  - Retinal Vessels/cytology/*growth & development/metabolism
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - Mammalian target of rapamycin
OT  - Rapamycin
OT  - Retina
OT  - Ribosomal protein S6
OT  - Vascular development
OT  - Vascular endothelial growth factor
EDAT- 2014/12/03 06:00
MHDA- 2015/02/11 06:00
CRDT- 2014/12/03 06:00
PHST- 2014/06/05 00:00 [received]
PHST- 2014/10/29 00:00 [revised]
PHST- 2014/11/07 00:00 [accepted]
PHST- 2014/12/03 06:00 [entrez]
PHST- 2014/12/03 06:00 [pubmed]
PHST- 2015/02/11 06:00 [medline]
AID - S0014-4835(14)00301-7 [pii]
AID - 10.1016/j.exer.2014.11.005 [doi]
PST - ppublish
SO  - Exp Eye Res. 2014 Dec;129:127-34. doi: 10.1016/j.exer.2014.11.005. Epub 2014 Nov 
      8.