Endovascular Trophoblast Invasion: Implications for the Pathogenesis of Intrauterine Growth Retardation and Preeclampsia

Abstract

Maternal uteroplacental blood flow increases during pregnancy. Altered uteroplacental blood flow is a core predictor of abnormal pregnancy. Normally, the uteroplacental arteries are invaded by endovascular trophoblast and remodeled into dilated, inelastic tubes without maternal vasomotor control. Disturbed remodeling is associated with maintenance of high uteroplacental vascular resistance and intrauterine growth restriction (IUGR) and preeclampsia. Herein, we review routes, mechanisms, and control of endovascular trophoblast invasion. The reviewed data suggest that endovascular trophoblast invasion involves a side route of interstitial invasion. Failure of vascular invasion is preceded by impaired interstitial trophoblast invasion. Extravillous trophoblast synthesis of nitric oxide is discussed in relation to arterial dilation that paves the way for endovascular trophoblast. Moreover, molecular mimicry of invading trophoblast-expressing endothelial adhesion molecules is discussed in relation to replacement of endothelium by trophoblast. Also, maternal uterine endothelial cells actively prepare endovascular invasion by expression of selectins that enable trophoblast to adhere to maternal endothelium. Finally, the mother can prevent endovascular invasion by activated macrophage-induced apoptosis of trophoblast. These data are partially controversial because of methodological restrictions associated with limitations of human tissue investigations and animal studies. Animal models require special care when extrapolating data to the human due to extreme species variations regarding trophoblast invasion. Basal plates of delivered placentas or curettage specimens have been used to describe failure of trophoblast invasion associated with IUGR and preeclampsia; however, they are unsuitable for these kinds of studies, since they do not include the area of pathogenic events, i.e., the placental bed.

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

“…The more severe forms of early-onset PE and idiopathic FGR are thought to originate as a consequence of impaired trophoblast function, with limited EVT invasion into maternal decidua and underlying myometrium in the early stages of pregnancy. 78 Defective trophoblast differentiation and shallow invasion of trophoblasts are key lesions commonly observed in PE placentae. 79 Placentae from FGR pregnancies show reduced trophoblast cell proliferation, reduced villous vascularisation and elevated vascular impedance.…”

Role of Hypoxia-Inducible Transcription Factors 1α and 2α in the Regulation of Plasminogen Activator Inhibitor-1 Expression in a Human Trophoblast Cell Line

“…It was suggested that the gestational age dependent reduction in HIFs likely reflects their degradation in response to increasing oxygen concentration [42,43]. In support of this premise is the finding of increased placental expression of HIF-1α and HIF-2α in pregnancies complicated by PE [44], which are also characterized by placental hypoxia [1,3,45].…”

“…Successful placentation and maintenance of pregnancy requires that invasive and hemostatic processes in trophoblasts are tightly regulated [1][2][3][4]. The plasmin/plasminogen activator system plays a key role in modulating these pathways at the maternal-fetal interface [2,3].…”

“…Previous studies have used siRNAs to down-regulate HIF-1α and/or HIF-2α expression in cancer cell lines [26,28], but not in trophoblasts or trophoblast cell lines, and their effect on PAI levels was not examined. This study is relevant to PAI regulation in early pregnancy when the placenta is exposed to relatively hypoxic conditions (2−3% O 2 ) in the first 10 weeks of gestation [32], as well as to pregnancies complicated by PE which is associated with prolonged hypoxia and aberrant PAI-1 expression at the maternal-placental interface [1,4,14,15].…”

NK cells, hypoxia and trophoblast cell differentiation

“…5 Among the specialized differentiated trophoblast cells of the placentation site are populations of cells with the capacity to migrate, invade the uterine parenchyma and associate with the vasculature. 3,[6][7][8] These cell types are defined by their relationships with the uterine spiral arteries. Those cells located between blood vessels are referred to as interstitial invasive trophoblast cells, and those cells embedded within vessels and contributing to the replacement of the endothelium are termed endovascular invasive trophoblast cells.…”