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.
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.
Department of Molecular Pharmacology, Shirokane, Minato-ku, Tokyo, Japan.
Akane
A
Morita
Tsutomu
T
Nakahara
Naomichi
N
Abe
Yuki
Y
Kurauchi
Asami
A
Mori
Kenji
K
Sakamoto
Tohru
T
Nagamitsu
Kunio
K
Ishii
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011247:Pregnancy; D011799:Quinazolines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012171:Retinal Vessels / Q000002:abnormalities* / Q000196:embryology
D010671:Phenylurea Compounds; D011799:Quinazolines; C508488:N-(2-chloro-4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl)-N'-propylurea; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor
retina; vascular development; vascular endothelial growth factor; vascular patterning