Induction of Intrauterine Growth Restriction by Reducing Placental Vascular Growth with the Angioinhibin TNP-470

Abstract

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.

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

“…A previous study has shown that administration of the angiogenesis inhibitor TNP-470 to pregnant mice from day 10.5 to 18.5 results in diminished placental and fetal growth (21). The morphological analysis performed by the authors revealed that TNP-470 disturbed labyrinthine blood vessel growth in the placenta.…”

“…Indeed, overexpression of sFlt-1 and administration of TNP-470, an angiogenesis inhibitor, in pregnant animals impaired the placental vascular development and caused IUGR (18,21). Both decreased placental blood flow and the inhibitor delivered to the fetus may influence the fetal vascular development and result in changes to the architecture of the vascular network.…”

A legjelentősebb angiogeneticus gének méhlepényi expressziójának változásai a méhen belüli növekedési visszamaradás hátterében

“…Noha az érképződési zavar teljes mechanizmusának biológiai háttere egyelőre felderítetlen, az angiogeneticus faktorok működészavarát több szerző is erősen valószínűsíti [12,[23][24][25]. Míg állatkísérletekben első-sorban a VEGF-A csökkent működése eredményezte IUGR kialakulását, addig a humán mintán végzett vizsgálatok elsősorban a PlGF érintettségére utaló eredmé-nyeket mutattak [26][27][28][29][30].…”

Tumor endothelial marker 1–specific DNA vaccination targets tumor vasculature

“…Antiangiogenic compounds have been associated with defective luteogenesis, reproductive dysfunction, pregnancy loss, and teratogenesis (41)(42)(43). Previous studies have reported TEM1 expression in several tissues of the mouse embryo (22,44).…”