Uterine natural killer cells initiate spiral artery remodeling in human pregnancy

Abstract

Uterine spiral artery remodeling is required for successful human pregnancy; impaired remodeling is associated with pregnancy complications, including late miscarriage, preeclampsia, and fetal growth restriction. The molecular triggers of remodeling are not known, but it is now clear that there are "trophoblast-independent" and "trophoblast-dependent" stages. Uterine natural killer (uNK) cells are abundant in decidualized endometrium in early pregnancy; they surround spiral arteries and secrete a range of angiogenic growth factors. We hypothesized that uNK cells mediate the initial stages of spiral artery remodeling. uNK cells and extravillous trophoblast (EVT) cells were isolated from early pregnancy decidua and placenta. Chorionic plate arteries from full-term placentas and spiral arteries from nonpregnant myometrium were cultured with angiogenic growth factors or conditioned medium (CM) from uNK cells or EVT or uNK cell/EVT cocultures. In both vessel models, uNK cell CM induced disruption of vascular smooth muscle cells (VSMCs) and breakdown of extracellular matrix components. Angiopoietin (Ang)-1, Ang-2, interferon-γ, and VEGF-C also disrupted VSMC integrity with an Ang-2 inhibitor abrogating the effect of uNK cell CM. These results provide compelling evidence that uNK cells contribute to the early stages of spiral artery remodeling; failure of this process could contribute to pregnancy pathology.

Porphyromonas gingivalisand adverse pregnancy outcome

“…Experimental ablation of uNK cells in pregnant rats reduces EVT invasion and induces vascular and perivascular necrosis with fibrosis surrounding the artery [64]. Human uNK cells induce disruption of VSMC and breakdown of the extracellular matrix in vitro, possibly making the arteries more penetrable to EVT cells [65]. Their role in vascular remodeling is also implied by their phenotype.…”

Immunological role of vitamin D at the maternal–fetal interface

“…In view of the fact that vitamin D deficiency in humans (Bodnar et al 2007b) and mice (Liu et al 2013) has been linked to PET, it is interesting to speculate that uNK cells may play a role in the pathophysiology of this complication of pregnancy. uNK cells appear to play a pivotal role in spiral arteriole remodelling (Robson et al 2012) and the regulation of extravillous trophoblast invasion into decidua basalis and superficial myometrium through the production of local cytokines and chemokines (Lash et al 2010b). In mice lacking uNK cells, there is a failure of normal decidual artery modification, and decidual hypo-cellularity/necrosis is observed (Lash et al 2010a).…”

Decidual cytokines and pregnancy complications: focus on spontaneous miscarriage

“…However, this view is likely too simplistic as Th1 cytokines have also been shown to be essential for maintenance of pregnancy, e.g. IFN-γ is essential for successful pregnancy as it is pivotal in spiral artery remodelling and successful pregnancy outcome (Ashkar et al, 2000;Croy et al, 2003;Robson et al, 2012).…”