Effects of KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase, on Vascular Development of Placenta and Fetus of Mid Pregnancy in Mice

Abstract

Abstract. Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway during pregnancy contributes to several pathologic pregnancies, such as hypertension, preeclampsia, and intrauterine growth restriction, but its effects on the fetus have not been fully examined. To determine how inhibition of the VEGF signaling pathway affects the fetal vascular development of mid pregnancy, we treated pregnant mice daily with either the VEGF receptor-2 (VEGFR-2) tyrosine kinase inhibitor KRN633 (300 mg/kg, p.o.) or the vehicle from 13.5 to 15.5 day of pregnancy. On the 16.5 day of pregnancy, the vascular beds in the placenta and several organs of the fetus were visualized by fluorescent immunohistochemistry. All mice treated with KRN633 appeared healthy, and total numbers of fetuses per litter were unaffected. However, weights of the placenta and fetus from KRN633-treated mice were lower than those from the vehicle-treated ones. No external malformations and bleeding were observed in the placenta and fetus, whereas immunohistochemical analyses revealed that the vascular development in labyrinthine zone of placenta and fetal organs examined (skin, pancreas, kidney, and lung) were impaired by KRN633 treatment. These results suggest that inhibition of the VEGF signaling pathway during mid pregnancy suppresses vascular growth of both the placenta and fetus without obvious health impairments of mother mice and increases the risk of induction of intrauterine growth restriction.

KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Intrauterine Growth Restriction in Mice

“…We previously found that administration of KRN633 (300 mg/kg/day) to pregnant mice from E13.5 to E15.5 largely compromised the development of the labyrinthine vascular bed of the placenta (Wada et al, ). Similar observations were made using the angiogenesis inhibitor TNP‐470 (Rutland et al, ).…”

Use of erlotinib throughout pregnancy: A case-report of a patient with metastatic lung adenocarcinoma

“…Studies on rats and rabbits have evidenced that tyrosine kinase inhibitors alter placental angiogenesis, which is associated with toxicity for embryonic development, placental hemorrhage, visceral, neurologic and skeletal malformations, intrauterine growth restriction and fetal death [10,11]. Erlotinib has been reported as the cause of embryonic and fetal death in rabbits when administered at a dose that achieved plasma concentrations approximately 3 times higher than those used in humans.…”

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

“…Previous studies showed that the inhibition of angiogenesis in mid-pregnant mice restricted placental and fetal growth (Rutland et al, 2005;Lu et al, 2007;Wada et al, 2010). Impaired vascularization in the placenta and fetal organs appears to reduce blood supply to fetal tissues, thereby restricting fetal growth (Wada et al, 2010;Abe et al, 2013).…”

“…Impairment of the angiogenic process during midpregnancy is associated with preeclampsia and intrauterine growth restriction, both of which are serious complications of pregnancy (Koga et al, 2003;Maynard et al, 2003). Previous studies showed that the inhibition of angiogenesis in mid-pregnant mice restricted placental and fetal growth (Rutland et al, 2005;Lu et al, 2007;Wada et al, 2010). Impaired vascularization in the placenta and fetal organs appears to reduce blood supply to fetal tissues, thereby restricting fetal growth (Wada et al, 2010;Abe et al, 2013).…”