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

Abstract

We previously reported that treatment of mid-pregnant mice with KRN633, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, caused fetal growth restriction resulting from diminished vascularization in the placenta and fetal organs. In this study, we examined how the treatment of mid-pregnant mice with KRN633 affects the development and morphology of vascular components (endothelial cells, pericytes, and basement membrane) in the retinas of their newborn pups. Pregnant mice were treated with KRN633 (5 mg/kg) once daily from embryonic day 13.5 until the day of delivery. Vascular components were examined using immunohistochemistry with specific markers for each component. Radial vascular growth in the retina was slightly delayed until postnatal day 4 (P4) in the newborn pups of KRN633-treated mothers. On P8, compared with the pups of control mothers, the pups of KRN633-treated mothers exhibited decreased numbers of central arteries and veins and abnormal branching of the central arteries. No apparent differences in pericytes or basement membrane were observed between the pups of control and KRN633-treated mothers. These results suggest that a critical period for determining retinal vascular patterning is present at the earliest stages of retinal vascular development, and that the impaired vascular endothelial growth factor signaling during this period induces abnormal architecture in the retinal vascular network.

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

“…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 ).…”

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

“…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.…”

Association of serum levels of vascular endothelial growth factor and placental growth factor in early threatened abortion and premature delivery: A case‑control study

“…VEGF serves a role in the physiological or pathological anti-placental formation and f previous studies have reported that VEGF is involved in placental angiogenesis (19,20). In the present study, the mean serum level of VEGF in patients with TA was 62.15±10.87 pg/ml, compared with 84.39±10.00 pg/ml in patients with healthy pregnancies.…”