title: KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, induces intrauterine growth restriction in mice.
abstract: 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.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Abe
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakahara
authors.forename: Akane
authors.initials: A
authors.lastname: Morita
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Wada
authors.forename: Asami
authors.initials: A
authors.lastname: Mori
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Tohru
authors.initials: T
authors.lastname: Nagamitsu
authors.forename: Kunio
authors.initials: K
authors.lastname: Ishii
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000473:pathology*; D007421:Intestine, Small / Q000098:blood supply / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D008221:Lymphoid Tissue / Q000098:blood supply / Q000187:drug effects; D008297:Male; D051379:Mice; D010179:Pancreas / Q000098:blood supply / Q000187:drug effects; D010671:Phenylurea Compounds / Q000633:toxicity*; D010920:Placenta / Q000098:blood supply / Q000187:drug effects; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011799:Quinazolines / Q000633:toxicity*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C508488:N-(2-chloro-4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl)-N'-propylurea; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: intrauterine growth restriction; placenta; vascular development; vascular endothelial growth factor