Grant sponsors: Scientific Research on Innovative Areas (Grant number: 23122517); Research Foundation for Pharmaceutical Sciences.
KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Intrauterine Growth Restriction in Mice
Article first published online: 18 JUN 2013
© 2013 Wiley Periodicals, Inc.
Birth Defects Research Part B: Developmental and Reproductive Toxicology
Volume 98, Issue 4, pages 297–303, August 2013
How to Cite
Abe, N., Nakahara, T., Morita, A., Wada, Y., Mori, A., Sakamoto, K., Nagamitsu, T. and Ishii, K. (2013), KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Intrauterine Growth Restriction in Mice. Birth Defects Research Part B: Developmental and Reproductive Toxicology, 98: 297–303. doi: 10.1002/bdrb.21064
- Issue published online: 15 OCT 2013
- Article first published online: 18 JUN 2013
- Manuscript Accepted: 19 APR 2013
- Manuscript Received: 22 FEB 2013
- Scientific Research on Innovative Areas 23122517
- Research Foundation for Pharmaceutical Sciences
- intrauterine growth restriction;
- vascular endothelial growth factor;
- vascular development
We previously reported that treatment with KRN633, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, during mid-pregnancy caused intrauterine growth restriction resulting from impairment of blood vessel growth in the labyrinthine zone of the placenta and fetal organs. However, the relative sensitivities of blood vessels in the placenta and fetal organs to vascular endothelial growth factor (VEGF) inhibitors have not been determined. In this study, we aimed to examine the effects of KRN633 on the vasculatures of organs in mother mice and their newborn pups by immunohistochemical analysis. Pregnant mice were treated daily with KRN633 (5 mg/kg) either from embryonic day 13.5 (E13.5) to E17.5 or from E13.5 to the day of delivery. The weights of the pups of KRN633-treated mice were lower than those of the pups of vehicle-treated mothers. However, no significant difference in body weight was observed between the vehicle- and KRN633-treated mice. The vascular development in the organs (the pancreas, kidney, and intestine) and intestinal lymphatic formation of the pups of KRN633-treated mothers was markedly impaired. In contrast, the KRN633 treatment showed no significant effect on the vascular beds in the organs, including the labyrinthine zone of the placenta, of the mother mice. These results suggest that blood vessels in fetal organs are likely to be more sensitive to reduced VEGF signaling than those in the mother. A partial loss of VEGF function during pregnancy could suppress vascular growth in the fetus without affecting the vasculature in the mother mouse, thereby increasing the risk of intrauterine growth restriction.