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

Journal of Pharmacological Sciences

Hiroaki Ohta¹  Kunio Ishii³  Tohru Nagamitsu²  Naomichi Abe³  Yoshiko Wada³  Tsutomu Nakahara³  Hiromi Ozaki³ 

[1] Department of Obstetrics and Gynecology, Tokyo Women’s Medical University, Japan;Department of Organic Synthesis, Kitasato University School of Pharmaceutical Sciences, Japan;Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Japan

关键词: fetus;    intrauterine growth restriction;    placenta;    vascular endothelial growth factor (VEGF);    vascular development;   

DOI  :  10.1254/jphs.09299FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(41)Cited-By(9)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.

【 授权许可】

Unknown