Treatment of Mid‐Pregnant Mice with KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Abnormal Retinal Vascular Patterning in Their Newborn Pups

Morita, Akane; Nakahara, Tsutomu; Abe, Naomichi; Kurauchi, Yuki; Mori, Akira; Sakamoto, Kenji; Nagamitsu, Tohru; Ishii, Kunio

doi:10.1002/bdrb.21112

Cited by 7 publications

(4 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Vascularization plays an important role in the early stage of testis and placenta development ( Brennan et al 2002 ; McClelland et al 2012 ; Reynolds and Redmer 2001 ). Although the testis and placenta play different roles in prenatal regulation of steroidogenesis in humans and rodents ( Scott et al 2009 ), the present study supports the hypothesis that vascular disruption is a key event in MRDT, similar to pregnancy loss and other birth defects ( Abe et al 2013 ; Kleinstreuer et al 2011 ; Morita et al 2014 ). Several molecular targets were identified in the IL-6 pathway (CSNK2A1, MAPK3, IL6, JUN, STAT3, and FOS), but previous knockout studies failed to show that the IL-6 pathway was critical to rodent embryo development ( Sakurai et al 2012 , 2013 ; Yoshida et al 2011 ).…”

Section: Discussionsupporting

confidence: 85%

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

Leung

Phuong

Baker

et al. 2016

Environ Health Perspect

View full text Add to dashboard Cite

Background:Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.Objective:In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.Methods:We used U.S. EPA’s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features.Results:A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network.Conclusion:Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s.Citation:Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050–1061; http://dx.doi.org/10.1289/ehp.1510385

show abstract

Section: Discussionsupporting

confidence: 85%

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

Leung

Phuong

Baker

et al. 2016

Environ Health Perspect

View full text Add to dashboard Cite

show abstract

“…Such gross abnormalities presumably arose shortly after birth since the critical window for the initial patterning of the retinal vasculature commences during this early postnatal window. 41,42 Our observations are also consistent with various comparable mouse retinopathy models where decreased vascular complexity and tortuous vessels were consistently observed. [43][44][45][46] Moreover, major vessel tortuosity often leads to long-term vision loss due to blood flow instability and hemodynamic disturbances.…”

Section: Discussionsupporting

confidence: 90%

Reduced mTORC1‐signaling in retinal ganglion cells leads to vascular retinopathy

Jones

Hägglund

Carlsson

2021

Developmental Dynamics

View full text Add to dashboard Cite

Background: The coordinated wiring of neurons, glia and endothelial cells into neurovascular units is critical for central nervous system development. This is best exemplified in the mammalian retina where interneurons, astrocytes and retinal ganglion cells sculpt their vascular environment to meet the metabolic demands of visual function. Identifying the molecular networks that underlie neurovascular unit formation is an important step towards a deeper understanding of nervous system development and function. Results: Here, we report that cell-to-cell mTORC1-signaling is essential for neurovascular unit formation during mouse retinal development. Using a conditional knockout approach we demonstrate that reduced mTORC1 activity in asymmetrically positioned retinal ganglion cells induces a delay in postnatal vascular network formation in addition to the production of rudimentary and tortuous vessel networks in adult animals. The severity of this vascular phenotype is directly correlated to the degree of mTORC1 down regulation within the neighboring retinal ganglion cell population.Conclusions: This study establishes a cell nonautonomous role for mTORC1-signaling during retinal development. These findings contribute to our current understanding of neurovascular unit formation and demonstrate how ganglion cells actively sculpt their local environment to ensure that the retina is perfused with an appropriate supply of oxygen and nutrients.

show abstract

“…After completing 96 hr of hyperoxia, only a few blood vessels in the optic nerve head were found on P4 (Fig. In spite of the delayed vascularization, retinal growth was unaffected by an episode of hyperoxia, as indi- Mice with an episode of 2-day inhibition of VEGFR on P0 and P1 exhibited fewer arteries and veins (Morita et al, 2014a(Morita et al, , 2014b(Morita et al, , 2014c. Retinal vascularization was markedly delayed (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Arteries and veins could be identified based on morphological criteria. For example, arteries tend to be smaller in diameter than veins and can be identified by capillary-free zones, which veins lack (Morita et al, 2014a(Morita et al, , 2014b(Morita et al, , 2014c. We collected both eyes, but data obtained from one eye were used for analyses of the retinal vascularization and the vessel number.…”

Section: Quantitative Analysis Of Endothelial Cell and Astrocyte Netwmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Treatment of Mid‐Pregnant Mice with KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Abnormal Retinal Vascular Patterning in Their Newborn Pups

Cited by 7 publications

References 23 publications

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

Reduced mTORC1‐signaling in retinal ganglion cells leads to vascular retinopathy

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

Contact Info

Product

Resources

About