Adaptive mechanisms controlling uterine spiral artery remodeling during the establishment of pregnancy

Abstract

Implantation of the embryo into the uterus triggers the initiation of hemochorial placentation. The hemochorial placenta facilitates the acquisition of maternal resources required for embryo/fetal growth. Uterine spiral arteries form the nutrient supply line for the placenta and fetus. This vascular conduit undergoes gestation stage-specific remodeling directed by maternal natural killer cells and embryo-derived invasive trophoblast lineages. The placentation site, including remodeling of the uterine spiral arteries, is shaped by environmental challenges. In this review, we discuss the cellular participants controlling pregnancy-dependent uterine spiral artery remodeling and mechanisms responsible for their development and function.

Fig. 1. Hemochorial placentation

Schematic diagram showing homologous structures within human and rat hemochorial placentation sites. In the human, trophoblast cells destined for the maternal compartment are referred to as extravillous trophoblast cells, whereas in the rat these cells are referred to as invasive trophoblast cells. Invasive trophoblast cells are specialized into interstitial and endovascular subtypes. Collectively, invasive trophoblast cells and natural killer cells direct uterine spiral artery restructuring. Adapted from Soares et al. 2012.

Fig. 2. Overview of the developmental progression from a totipotent stem cell to a multipotent trophoblast stem (TS) cell to a specialized differentiated trophoblast cell

Each step along the developmental progression is controlled by positive and negative modulatory factors. These factors can be characterized as transcription factors, histone modifiers, and chromatin organizers (lists are provided in boxes below each cell type). See text for additional information.

Fig. 3. Maternal hypoxia stimulates trophoblast invasion into uterine spiral arteries of the rat

Wild-type female rats were mated to homozygous chβA-enhanced green fluorescent protein (EGFP) transgenic male rats and exposed to an atmospheric oxygen tension (21 percent at sea level; panel A) or hypoxia (10-11%; gestation day 6.5 to day 13.5; panel B). Placentation sites were examined on gestation day 13.5 and uterine mesometrial compartments inspected for EGFP positive cells. Note that maternal hypoxia stimulated the invasion of extraembryonic-derived EGFP positive cells deep into maternal uterine spiral arteries, representing a potentially effective placental-associated adaptation to an environmental challenge. Scale bar = 0.5 mm. Adapted from Rosario et al. 2008.

Fig. 4. Trophoblast stem (TS) cell plasticity and placental disease

Environmental challenges, including nutrient availability, at the maternal-fetal interface direct the decision-making of TS cells. TS cells possess the capacity to self-renew, die, become quiescent, or differentiate into specialized trophoblast lineages. A successful pregnancy is associated with robust and gestation stage-appropriate homeostatic responses to environmental challenges resulting in effective organization of the placentation site, maternal adaptations and normal progression of fetal development and healthy offspring. In contrast, we propose that placental disease is associated with a TS cell that lacks plasticity and the ability to effectively adapt to environmental challenges, which activates a positive feedback loop sustaining and potentially intensifying the environmental challenge, resulting in failures in placentation and maternal, fetal, and postnatal compromise.