Abstract
Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in intrauterine fetal death.
Highlights
Normal placental vascular growth and remodeling are required for transferring oxygen, nutrients and metabolites between maternal system and fetal system to support fetal growth [1]
There was no impairment and detectable abnormality in daily behavior, general condition, or food consumption in the dams treated with 8.0 mg/kg bw TCDD compared with other groups during pregnancy
The placental and fetal weights were similar among all ITE-exposed, TCDD-exposed groups and vehicle-control (Fig. 1 A–B). These indicate that ITE serves as a nontoxic agent which does not induce intrauterine fetal death even though the low dose of TCDD might not be enough to cause adverse effects on rat reproductive outcomes compared to the higher dose of TCDD
Summary
Normal placental vascular growth and remodeling are required for transferring oxygen, nutrients and metabolites between maternal system and fetal system to support fetal growth [1]. Any impaired placental vascular development will lead to adverse effects on both mother and fetus, possibly leading to preeclampsia, abortion and intrauterine growth retardation [1,2,3,4]. The rapid placental vascular growth and remodeling occur between gestational day (GD) to GD20 as the placenta blood flow increases exponentially in order to nourish the rapid growth of fetus [5,6]. The establishment and remodeling of the placental blood vessels are regulated by a broad spectrum of angiogenic-associated factors and their receptors, including of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system and Angiopoietin (Ang)/Tie system and cytokines, etc. Placental vascular development can be stimulated under a hypoxic condition because the activation of HIF-1a leads to the adaptation of hypoxia, and activates the transcription of VEGF/VEGFR system and regulates the expression of VEGF and fms-like tyrosine kinase-1 (Flt-1) [7,10,11]
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