Induction of intrauterine growth restriction by reducing placental vascular growth with the angioinhibin TNP-470.
The placenta is a specialized vascular interface between the maternal and fetal circulations that increases in size to accommodate the nutritional and metabolic demands of the growing fetus. Vascular proliferation and expansion are critical components of placental development and, consequently, interference with vascular growth has the potential to severely restrict concurrent development of both the placenta and fetus. In this study, we describe the effects of an antiangiogenic agent, TNP-470, on placental vascular development and the induction of a form of intrauterine growth restriction (IUGR) in mice. Administration of TNP-470 to dams in the second half of pregnancy resulted in a smaller maternal weight gain accompanied by decreased placental and fetal sizes in comparison with control animals. Total numbers of fetuses per litter were not affected significantly. Stereological analysis of placentas revealed no changes in the combined lengths of vessels. However, the mean cross-sectional areas of maternal and fetal vessels in the labyrinth of TNP-470-treated mice were reduced at Embryonic Day 13.5 (E13.5) but not at E18.5. Further analysis showed reduced placental endothelial proliferation at E13.5 and E18.5 in TNP-470-treated animals. No other structural or morphometric differences in placentas were detected between TNP-470-treated and control mice at E18.5. This study provides conclusive evidence that administration of TNP-470 interferes with placental vascular proliferation and vessel caliber and results in a reproducible model of IUGR.
Rutland
Catrin S
CS
School of Biomedical Sciences, University of Nottingham, Nottingham, NG7 2UH United Kingdom.
Mukhopadhyay
Mallinath
M
Underwood
Suzanne
S
Clyde
Norma
N
Mayhew
Terry M
TM
Mitchell
Christopher A
CA
D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects / Q000378:metabolism; D003510:Cyclohexanes; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced* / Q000503:physiopathology; D005865:Gestational Age; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000166:cytology / Q000187:drug effects; D010929:Placentation / Q000187:drug effects*; D011247:Pregnancy; D012717:Sesquiterpenes / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003510:Cyclohexanes; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; D000077609:O-(Chloroacetylcarbamoyl)fumagillol