The role of extravillous trophoblasts and uterine NK cells in vascular remodeling during pregnancy

Abstract

Successful embryo implantation requires both a receptive endometrium and competent blastocysts. After implantation, the maternal decidua undergoes a series of changes, including uterine spiral artery (SA) remodeling to accommodate the fetus and provide nutrients and oxygen for the fetus to survive. Uterine spiral arteries transform from small-diameter, high-resistance arteries to large-diameter and low-resistance arteries during pregnancy. This transformation includes many changes, such as increased permeability and dilation of vessels, phenotypic switching and migration of vascular smooth muscle cells (VSMCs), transient loss of endothelial cells (ECs), endovascular invasion of extravillous trophoblasts (EVTs), and presence of intramural EVT, which are regulated by uterine NK (uNK) cells and EVTs. In this review, we mainly focus on the separate and combined roles of uNK cells and EVTs in uterine SA remodeling in establishing and maintaining pregnancy. New insight into related mechanisms will help us better understand the pathogenesis of pregnancy complications such as recurrent pregnancy loss (RPL) and preeclampsia (PE).

Keywords: extravillous trophoblast (EVT); preeclampsia (PE); recurrent pregnancy loss (RPL); spiral artery remodeling; uterine natural killer cells.

Figure 1

The interaction between EVT and uNK cells during pregnancy. The blastocyst mainly consists of two structures called the inner cell mass and the trophectoderm, which differentiate into fetus and placenta, respectively. During the formation of the placenta, the trophectoderm transforms into mononuclear CTBs, which have two differentiation ways. CTBs can fuse into multinuclear STBs and form the syncytial layer. Proliferative but non-invasive CTBs can switch to invasive but non-proliferative EVT, forming a stratified structure called the cell column. EVTs that migrate into the maternal decidua are called interstitial EVTs (iEVT) and further develop into endovascular trophoblasts (eEVT) that migrate through the spiral arteries. The direct or indirect interaction of uNK cells with EVT has been shown to facilitate the induction and maintenance of immune tolerance, protect the placenta against pathogen infection, and promote SA remodeling. Uterine environment including hormones and oxygen tension at the maternal-fetal interface plays an important role in regulating EVT and uNK cells during pregnancy. HLA-C, -G, and -E expressed by EVTs have been demonstrated to be ligands of either activating or inhibitory uNK cell receptors, providing a delicate balance between tolerance of trophoblast from maternal immune response and cytolytic activation of uNK. HLA-G is mainly expressed in EVT and believed to be a critical factor to prevent maternal immune attack to semi-allogenic fetus, while polymorphic HLA-C can elicit a maternal immune response. The interaction between HLA-G and ILT2 can also contribute to the release of proangiogenic factors. Engagement of activating KIR with HLA-C can reduce the risk of pregnancy complications, possibly through providing specific immunity to viral and bacterial pathogens. NKG2A/C/E could engage with its ligand HLA-E to regulate placental function and immune adaptation. uNK cells surround the spiral arteries and secrete many factors such as Ang-1, Ang-2, and IFN-γ, which can disrupt the integrity of VSMC and mediate extracellular matrix degradation. IFN-γ derived from uNK cells could upregulate the MEG3 and increase the expression of MMP-2, thus promoting VSMCs apoptosis and migration. Exosomes derived from EVTs may promote the migration of VSMCs out of vessel walls and lead to uterine SA remodeling. uNK cells can transmit granulysin into EVT via nanotubes and kill intracellular bacterial without damaging EVT. (uNK cells, uterine natural killer cells; EVT, extravillous trophoblast; CTBs, cytotrophoblasts; STBs, syncytiotrophoblasts; iEVT, interstitial EVTs; eEVT, endovascular trophoblasts; SA, spiral artery; HLA, human leukocyte antigen; ILT2, Ig-like transcript 2; KIR, Killer-cell immunoglobulin-like receptors; NKG2A/C/E, CD94/NK group 2 member A/C/E; Ang-1, Angiopoietin-1; IFN-γ, interferon-γ; VSMC, vascular smooth muscle cell; MEG3, maternally expressed 3; MMP2, matrix metalloproteinase-2).