Paradigms for investigating invasive trophoblast cell development and contributions to uterine spiral artery remodeling

Abstract

Uterine spiral arteries are extensively remodeled during placentation to ensure sufficient delivery of maternal blood to the developing fetus. Uterine spiral arterial remodeling is complex, as cells originating from both mother and developing conceptus interact at the maternal interface to regulate the extracellular matrix remodeling and vasculature restructuring necessary for successful placentation. Despite this complexity, one mechanism critical to spiral artery remodeling is trophoblast cell invasion into the maternal compartment. Invasive trophoblast cells include both interstitial and endovascular populations that exhibit spatiotemporal differences in uterine invasion, including proximity to uterine spiral arteries. Interstitial trophoblast cells invade the uterine parenchyma where they are interspersed among stromal cells. Endovascular trophoblast cells infiltrate uterine spiral arteries, replace endothelial cells, adopt a pseudo-endothelial cell phenotype, and engineer vessel remodeling. Impaired trophoblast cell invasion and, consequently, insufficient uterine spiral arterial remodeling can lead to the development of pregnancy disorders, such as preeclampsia, intrauterine growth restriction, and premature birth. This review provides insights into invasive trophoblast cells and their function during normal placentation as well as in settings of disease.

Keywords: Extravillous; Hemochorial placentation; Hypoxia; Intrauterine invasion; Invasive trophoblast cells.

Figure 1.. Trophoblast cell invasion in the human and the rat.

Similar to the human, the rat possesses a hemochorial placenta with deep trophoblast invasion and extensive spiral artery remodeling. Trophoblast cells invade both interstitially and endovascularly through uterine spiral arteries where they replace endothelial cells and adopt a pseudo-endothelial cell phenotype. In the human, invasive extravillous trophoblast (EVT) cells are derived from cell progenitors residing in extravillous cell columns. The analogous site of trophoblast progenitors in the rat is the junctional zone.

Figure 2.. Endovascular trophoblast cell-regulated uterine spiral artery remodeling.

Endovascular trophoblast cells migrate through spiral arteries where they actively promote remodeling. As spiral artery remodeling progresses, vascular smooth muscle cells surrounding the arteries are removed and basement membrane is modified. Remodeling also involves removal of the endothelium and replacement by endovascular trophoblast cells which adopt a pseudo-endothelial phenotype. Many questions remain as to the significance of endovascular trophoblast cells replacing endothelial cells lining remodeled spiral arteries.