Circulating Maternal sFLT1 (Soluble fms-Like Tyrosine Kinase-1) Is Sufficient to Impair Spiral Arterial Remodeling in a Preeclampsia Mouse Model

One driving factor for developing preeclampsia—a pregnancy disorder, often associated with poor spiral artery (SpA)-remodeling and fetal growth restriction—is the anti-angiogenic sFLT1 (soluble fms-like tyrosine kinase-1), which is found to be highly upregulated in preeclampsia patients. The sFLT1-mediated endothelial dysfunction is a common theory for the manifestation of maternal preeclampsia symptoms. However, the influence of sFLT1 on SpA-remodeling and the link between placental and maternal preeclampsia symptoms is less understood. To dissect the hsFLT1 (human sFLT1) effects on maternal and/or fetoplacental physiology in preeclampsia, sFLT1-transgenic mice with systemic hsFLT1 overexpression from midgestation onwards were used. SpA-remodeling was analyzed on histological and molecular level in placental/mesometrial triangle tissues. Maternal kidney and aorta morphology was investigated, combined with blood pressure measurements via telemetry. hsFLT1 overexpression resulted in maternal hypertension, aortic wall thickening, and elastin breakdown. Furthermore, maternal kidneys showed glomerular endotheliosis, podocyte damage, and proteinuria. preeclampsia symptoms were combined with fetal growth restriction already at the end of the second trimester and SpA-remodeling was strongly impaired as shown by persisted vascular smooth muscle cells. This phenotype was associated with shallow trophoblast invasion, delayed presence of uterine natural killer cells, and altered lymphatic angiogenesis. Overall, this study showed that circulating maternal hsFLT1 is sufficient to induce typical maternal preeclampsia-like symptoms in mice and impair the SpA-remodeling independent from the fetoplacental compartment, revealing new insights into the interaction between the placental and maternal contribution of preeclampsia.

Immunological Testing in Assisted Reproductive Technology

Fetal implantation requires carefully orchestrated involvement of the maternal immune system. Aberrant function within implantation has been suggested as a cause of implantation failure. The emergence of immunological theories of miscarriage has led to immunological testing as an adjuvant treatment in assisted reproductive technology; however, it remains controversial, with mixed evidence both for immunological cause and the benefits of immunological testing. Literature on common methods of immunological testing within assisted reproductive technology is reviewed including those of peripheral and uterine natural killer cells, chronic endometritis, and T-helper cells cytokine ratio. There is little consensus in the evidence on immunological testing in the context of recurrent implantation failure. The field is limited by a lack of uniformity in approach to testing and heterogeneity of the pathophysiological cause. Nevertheless, the maternal immune system is heavily involved in implantation and the new era of personalized medicine ensures that a more defined approach to immunological testing will be achieved.

Cannabinoid Signalling in Immune–Reproductive Crosstalk during Human Pregnancy

Despite the intricate involvement of the endocannabinoid system in various physiological processes, it remains one of the most under-studied biological systems of the human body. The scope of endocannabinoid signalling is widespread, ranging from modulation of immune responses in innate and adaptive immunity to gestational processes in female physiology. Cannabinoid receptors are ubiquitously distributed in reproductive tissues and are thought to play a role in regulating the immune–reproductive interactions required for successful pregnancy, specifically among uterine natural killer cells and placental extravillous trophoblasts. The use of cannabis during pregnancy, however, can perturb endocannabinoid homeostasis through effects mediated by its major constituents, Δ-9-tetrahydrocannabinol and cannabidiol. Decidualization of the endometrium, invasion, and angiogenesis may be impaired as a consequence, leading to clinical complications such as miscarriage and preeclampsia. In this review, the crosstalk between endocannabinoid signalling in uterine natural killer cells and placental extravillous trophoblasts will be examined in healthy and complicated pregnancies. This lays a foundation for discussing the potential of targeting the endocannabinoid system for therapeutic benefit, particularly with regard to the emerging field of synthetic cannabinoids.

The Lipiodol Uterine Bathing Effect to Improve Fertility May Include Uterine Natural Killer Cell Up-regulation in the Endometrium

BACKGROUND: Lipiodol has a dramatic short term fertility enhancing effect for women with endometriosis. Microarray studies have shown transcriptomic regulation of molecular markers of endometrial inflammation, most notably a consistent down-regulation of endometrial osteopontin. We further explored the endometrial bathing effect of lipiodol on leukocyte expression in endometrium. METHODS: A cohort of four women, nested within a randomised trial of twelve women assessing the lipiodol uterine bathing effect, was studied as an ‘own control’ group, with their mid-luteal endometrium assessed before and after endometrial lipiodol exposure. Pipelle endometrial sampling allowed endometrial assessment by immunochemistry. Endometrial tissue samples were assessed by immunochemistry for total CD45+ leukocytes, CD68+ macrophages, CD3+ T-cells and CD56+ uterine natural killer cells. RESULTS: There was a statistically significant increase in the mean density of uterine natural killer cells in the endometrium of women post-lipiodol. No other significant differences were found in the mean densities of all leukocytes, macrophages or T cells in the endometrium of women post-lipiodol. CONCLUSIONS: These preliminary data further support the concept of a uterine bathing effect of lipiodol. Whether the increase in the mean density of uterine natural killer cells in the endometrium might contribute to an improvement in endometrial receptivity to embryo implantation merits further investigation.

Immune Tolerance of the Human Decidua

The endometrium is necessary for implantation, complete development of the placenta, and a successful pregnancy. The endometrium undergoes repeated cycles of proliferation, decidualization (differentiation), and shedding during each menstrual cycle. The endometrium—including stromal, epithelial, vascular endothelial, and immune cells—is both functionally and morphologically altered in response to progesterone, causing changes in the number and types of immune cells. Immune cells make up half of the total number of endometrial cells during implantation and menstruation. Surprisingly, immune tolerant cells in the endometrium (uterine natural killer cells, T cells, and macrophages) have two conflicting functions: to protect the body by eliminating pathogenic microorganisms and other pathogens and to foster immunological change to tolerate the embryo during pregnancy. One of the key molecules involved in this control is the cytokine interleukin-15 (IL-15), which is secreted by endometrial stromal cells. Recently, it has been reported that IL-15 is directly regulated by the transcription factor heart- and neural crest derivatives-expressed protein 2 in endometrial stromal cells. In this review, we outline the significance of the endometrium and immune cell population during menstruation and early pregnancy and describe the factors involved in immune tolerance and their involvement in the establishment and maintenance of pregnancy.

The Role of NF-κB in Uterine Spiral Arteries Remodeling, Insight into the Cornerstone of Preeclampsia

Preeclampsia is one of the three leading causes of maternal morbidity and mortality worldwide. It afflicts 2–8% of pregnancies and is the most common cause of gestational hypertension. This article is focused on nuclear factor kappa B (NF-κB), its role in normal and pathological spiral arteries remodelling and development of preeclampsia, with evaluation if it is a promising therapeutic target. NF-κB is a key mediator of placentation. Since insemination, it stimulates production of proinflammatory cytokines by the uterine epithelium, which leads to activation of macrophages, uterine natural killer cells (uNKs), and other leukocytes. The trophoblast/uNK/macrophage crosstalk is crucial for implantation and spiral arteries remodeling, and NF-κB regulates that process through modification of cytokine expression, as well as cell phenotype and function. In the course of preeclampsia, the remodeling processes is disturbed by excessive inflammation and increased NF-κB activation. The pathological remodeling leads to uteroplacental dysfunction, release of proinflammatory cytokines into the maternal circulation, endothelial stress, and development of preeclampsia. The analysis of genetic and environmental inductors of NF-κB helps to distinguish preeclampsia risk groups. Furthermore, a selective inhibition of NF-κB or NF-κB activating pathways alleviates symptoms of preeclampsia in rat models; therefore, this could be an efficient therapeutic option.