Effects of mTOR inhibition on normal retinal vascular development in the mouse

Yagasaki, Rina; Nakahara, Tsutomu; Mori, Akira; Sakamoto, Kenji; Ishii, Kunio

doi:10.1016/j.exer.2014.11.005

Cited by 20 publications

(21 citation statements)

References 21 publications

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“…Therefore, the delay of retinal vascularization seems to develop severe retinal hypoxia in avascular areas, which leads to an elevation in VEGF expression. The pattern of distribution of VEGF mRNA resembles that of an astrocyte network (Gerhardt et al, 2003;Yagasaki et al, 2014b). Consistently, triple labeling of retinas with VEGF, isolectin B4, and PDGFR indicated that VEGF immunoreactivity was colocalized to PDGFR -stained astrocytes in vascular front and avascular areas in the retina, and VEGF immunoreactivity was enhanced in hyperoxia-exposed mice (Supporting Information Fig.…”

Section: As Shown Insupporting

confidence: 56%

“…3A). The pattern of distribution of VEGF mRNA resembles that of an astrocyte network (Gerhardt et al, 2003;Yagasaki et al, 2014b). The densities of both endothelial cells and astrocytes in hyperoxia-exposed mice were higher than those in control mice (Fig.…”

Section: As Shown Inmentioning

confidence: 76%

“…The VEGF mRNA distribution was determined by whole-mount in situ hybridization, as reported previously (Morita et al, 2014a;Yagasaki, Nakahara, Mori, Sakamoto, & Ishii, 2014b). After completing the in situ hybridization protocol, the vascular network was visualized by antitype IV collagen antibody (1:2000; Cosmo Bio, Tokyo, Japan) labeling.…”

Section: In Situ Hybridization Of Whole-mount Retinasmentioning

confidence: 99%

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Exposure to high‐concentration oxygen in the neonatal period induces abnormal retinal vascular patterning in mice

Morita

Ushikubo

Mori

et al. 2016

Birth Defects Research Pt B

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The interruption of vascular development could cause structural and functional abnormalities in tissues. We have previously reported that short-term treatment of newborn mice with vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors induces abnormal retinal vascular growth and patterns. An exposure of neonatal mice to high-concentration oxygen disturbs normal retinal vascular development. The present study aimed to determine (1) whether vascular abnormalities are observed in the retina of newborn mice exposed to high concentrations of oxygen, and (2) how astrocyte network formation is affected following the exposure to hyperoxia. Newborn (postnatal day 0) mice were exposed to 75% oxygen for 48 or 96 hr. During hyperoxia exposure, VEGF expression decreased, and the onset of retinal vascularization was completely suppressed. After completion of the hyperoxic period, retinal vascularization occurred, but it was delayed in a hyperoxic exposure duration-dependent manner. In retinas of hyperoxia-exposed mice, dense capillary plexuses were found, and the number of arteries and veins decreased. The astrocyte network formation was slightly delayed under hyperoxic conditions, and the network became denser in retinas of mice with an episode of hyperoxia. Expression of VEGF levels in the avascular retina of mice that were exposed to hyperoxia was higher than that of control mice. These results suggest that short-term interruption of the onset of vascular development resulting from the reduction in VEGF signals induces abnormal vascular patterns in the mouse retina. The abnormalities in retinal astrocyte behavior might contribute to the formation of an abnormal retinal vascular growth.

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Section: As Shown Insupporting

confidence: 56%

Section: As Shown Inmentioning

confidence: 76%

Section: In Situ Hybridization Of Whole-mount Retinasmentioning

confidence: 99%

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Exposure to high‐concentration oxygen in the neonatal period induces abnormal retinal vascular patterning in mice

Morita

Ushikubo

Mori

et al. 2016

Birth Defects Research Pt B

Self Cite

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“…In mouse retina, several cell types such as astrocytes, neuronal cells, and M€ uller cells express VEGF (Feeney et al, 2003;Okabe et al, 2014;Yagasaki et al, 2014;Morita et al, 2017). Although the most predominant cell type as a source of VEGF is unclear, the pattern of distribution of VEGF mRNA and protein in the avascular area resembled that of an astrocyte network, and our immunohistochemical studies revealed that VEGF protein is expressed in PDGFRa-positive astrocytes.…”

Section: Discussionmentioning

confidence: 65%

“…The susceptibility of retinal endothelial cells to loss of VEGF signals was reduced in an agedependent manner (Ozaki et al, 2000). The effects of KRN633 on retinal blood vessels decreased during the first postnatal week (Yagasaki et al, 2014). Therefore, we hypothesized that neonatal mice treated with KRN633 at different time points during the first postnatal week would exhibit different degrees and patterns of disturbance of retinal vascular development.…”

Section: Introductionmentioning

confidence: 99%

Transient phenotypic changes in endothelial cells and pericytes in neonatal mouse retina following short‐term blockade of vascular endothelial growth factor receptors

Morita

Mori

Arima

et al. 2018

Developmental Dynamics

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AAV expressing an mTOR‐inhibiting siRNA exhibits therapeutic potential in retinal vascular disorders by preserving endothelial integrity

Cha¹,

Seo

Woo

et al. 2021

FEBS Open Bio

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Expanding on previous demonstrations of the therapeutic effects of adeno-associated virus (AAV) carrying small-hairpin RNA (shRNA) in downregulating the mechanistic target of rapamycin (mTOR) in in vivo retinal vascular disorders, vascular endothelial growth factor (VEGF)-stimulated endothelial cells were treated with AAV2-shmTOR to examine the role of mTOR inhibition in retinal angiogenesis. AAV2-shmTOR exposure significantly reduced mTOR expression in human umbilical vein endothelial cells (HUVECs) and decreased downstream signaling cascades of mTOR complex 1 (mTORC1) and mTORC2 under VEGF treatment. Moreover, the angiogenic potential of VEGF was significantly inhibited by AAV2-shmTOR, which preserved endothelial integrity by maintaining tight junctions between HUVECs. These data thus support previous in vivo studies and provide evidence that AAV2-shmTOR induces therapeutic effects by inhibiting the neovascularization of endothelial cells.

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Effects of mTOR inhibition on normal retinal vascular development in the mouse

Cited by 20 publications

References 21 publications

Exposure to high‐concentration oxygen in the neonatal period induces abnormal retinal vascular patterning in mice

Exposure to high‐concentration oxygen in the neonatal period induces abnormal retinal vascular patterning in mice

Transient phenotypic changes in endothelial cells and pericytes in neonatal mouse retina following short‐term blockade of vascular endothelial growth factor receptors

AAV expressing an mTOR‐inhibiting siRNA exhibits therapeutic potential in retinal vascular disorders by preserving endothelial integrity

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