Uterine Spiral Artery Remodeling: The Role of Uterine Natural Killer Cells and Extravillous Trophoblasts in Normal and High‐Risk Human Pregnancies

Abstract

The process of uterine spiral artery remodeling in the first trimester of human pregnancy is an essential part of establishing adequate blood perfusion of the placenta that will allow optimal nutrient/waste exchange to meet fetal demands during later development. Key regulators of spiral artery remodeling are the uterine natural killer cells and the invasive extravillous trophoblasts. The functions of these cells as well as regulation of their activation states and temporal regulation of their localization within the uterine tissue are beginning to be known. In this review, we discuss the roles of these two cell lineages in arterial remodeling events, their interaction/influence on one another and the outcomes of altered temporal, and spatial regulation of these cells in pregnancy complications.

Dynamics of Immune Cell Types Within the Macaque Corpus Luteum During the Menstrual Cycle: Role of Progesterone1

“…One function of neutrophils is to induce NK cell maturation [40]. The majority of research to date on NK cell function in the reproductive tract focuses on their role during embryo implantation and placentation within the uterus [44]. It is important to mention that the majority of primate uterine NK cells are CD56 bright , and increased numbers of CD56 dim NK cells in the uterus are associated with reproductive failure [45].…”

“…The function of NK cells has yet to be studied in the non-neoplastic ovary, however, there are some reports on use of peripheral cytotoxic NK cells as a therapy for ovarian cancer [48,49]. Because NK cells appear to promote placentation and uterine vascular remodeling [44], they may have a similar role in promoting vessel growth, maturation and stability during formation (early) and function (mid-to mid-late) of the CL, before assuming degenerative roles during luteal regression. NK cells may be considered the innate counterparts of cytotoxic T cells [4], and may switch from trophic to lytic roles during the lifespan of primate CL much as proposed for T cells in the CL of domestic animals [2,50].…”

Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta

“…Spiral artery remodeling, which increases total uteroplacental blood flow from a baseline value of 20-50 mL/min to 450-800 mL/min in singleton pregnancies (as measured utilizing the diffusion equilibrium principle [most often nitrous oxide] or electromagnetic flow probes placed directly on the uterine artery), is considered key to accommodate the increased blood flow to the uteroplacental circulation in the third trimester [1–7]. Initially, physiologic transformation of the spiral arteries includes endothelial vacuolation and smooth muscle swelling [8–11], and it has been attributed in part to immune processes within the decidua [4,12–18]. Subsequently, trophoblasts invading the spiral arteries destroy the smooth muscle in the media, which is replaced by fibrinoid material [1,3,19–21].…”

Inactivation of maternal Hif-1α at mid-pregnancy causes placental defects and deficits in oxygen delivery to the fetal organs under hypoxic stress

“…These maternally derived immune cells are recruited to the maternal decidua, and thought to play a role in the remodeling of the SAs (Chakraborty et al, 2011; Tessier et al, 2015). As expected Prf- positive uNK cells were abundant in E13.5 CON decidua and had significantly declined by E15.5 (Fig.…”

“…gain-of-function, to suggest a role for hypoxia/HIF in the recruitment of invasive trophoblasts into the maternal decidua for the purpose of uterine vascular remodeling (Rosario et al, 2008). uNK cells are also thought to be required for the initiation of uterine spiral artery remodeling in humans (Hanna et al, 2006), rats (Chakraborty et al, 2011) and mice (Ashkar et al, 2000; Guimond et al, 1998) (reviewed in (Soares et al, 2014; Tessier et al, 2015). NK cell depletion in the rat delayed spiral artery remodeling and increased Pimonidazole binding and HIF-1α protein in the placenta as markers of placental hypoxia (Chakraborty et al, 2011).…”