Acute Atherosis Lesions at the Fetal-Maternal Border: Current Knowledge and Implications for Maternal Cardiovascular Health

Decidua basalis, the endometrium of pregnancy, is an important interface between maternal and fetal tissues, made up of both maternal and fetal cells. Acute atherosis is a uteroplacental spiral artery lesion. These patchy arterial wall lesions containing foam cells are predominantly found in the decidua basalis, at the tips of the maternal arteries, where they feed into the placental intervillous space. Acute atherosis is prevalent in preeclampsia and other obstetric syndromes such as fetal growth restriction. Causal factors and effects of acute atherosis remain uncertain. This is in part because decidua basalis is challenging to sample systematically and in large amounts following delivery. We summarize our decidua basalis vacuum suction method, which facilitates tissue-based studies of acute atherosis. We also describe our evidence-based research definition of acute atherosis. Here, we comprehensively review the existing literature on acute atherosis, its underlying mechanisms and possible short- and long-term effects. We propose that multiple pathways leading to decidual vascular inflammation may promote acute atherosis formation, with or without poor spiral artery remodeling and/or preeclampsia. These include maternal alloreactivity, ischemia-reperfusion injury, preexisting systemic inflammation, and microbial infection. The concept of acute atherosis as an inflammatory lesion is not novel. The lesions themselves have an inflammatory phenotype and resemble other arterial lesions of more extensively studied etiology. We discuss findings of concurrently dysregulated proteins involved in immune regulation and cardiovascular function in women with acute atherosis. We also propose a novel hypothesis linking cellular fetal microchimerism, which is prevalent in women with preeclampsia, with acute atherosis in pregnancy and future cardiovascular and neurovascular disease. Finally, women with a history of preeclampsia have an increased risk of premature cardiovascular disease. We review whether presence of acute atherosis may identify women at especially high risk for premature cardiovascular disease.

Validation of Fetal Microchimerism after Pregnancy in the ovine using qPCR

Fetal microchimerism has been detected in maternal tissues of humans and rodents during and after pregnancy. Studies focusing on fetal DNA transfer to maternal tissues in domestic animals are limited, especially in sheep. Fetal ram DNA was observed in the maternal circulation during pregnancy, but it is not known if this chimerism persists in soft tissues after parturition. The objectives of this exploratory study were to: 1) determine if male fetal DNA is detectable in soft tissues of mature ewes after parturition and if so, determine if detection repeatability differed with lifetime offspring sex ratio and 2) determine if male fetal DNA was present in soft tissues of yearling (primiparous) ewes shortly after parturition. Eight mature (open, non-lactating) and 8 yearling (primiparous, periparturient) Rambouillet ewes were used. Mature ewes (5- to 7- years old) had given birth to primarily 82% males (n = 4) or 71% female (n = 4) over a lifetime. Yearling ewes had birthed either a singleton male (n = 4) or female (n = 4) lambs. DNA was extracted from 10 and 11 different soft tissues from the mature and yearling ewes, respectively. Real-time PCR (qPCR) was used to identify the presence of the SRY gene in each tissue sample. Male DNA was detected in the brain and liver from 1 mature open ewe that had given birth to 2 males and 6 females during her lifetime. In younger ewes that gave birth to a ram lamb, male DNA was observed in the thyroid of 1 ewe and the pancreas and brain of a second ewe. Male DNA was detected in the ovary of 1 ewe that had given birth to a female lamb. Based on these data, we suggest fetal microchimerism in soft maternal tissues is possible in sheep and may remain after pregnancy has ended. The detection repeatability of male fetal DNA was not associated with sex ratio of lifetime offspring. Male DNA was observed in maternal soft tissues collected shortly after parturition. The greater detection of fetal male DNA found in younger ewes shortly after parturition may be due to not having enough time for fetal DNA clearance to occur. Future studies are warranted to further study XY chimerism in maternal tissues of the ewe and its potential role in ovine physiology.

What do we know about fetal-maternal microchimerism?

Microchimerism is a condition characterized by the presence of a small number of foreign cells genetically different from the host cells. Thus, during pregnancy maternal and fetal cells cross the placental barrier, enter the foreign bloodstream and settle in the organs, which leads to the formation of fetal-maternal microchimerism. This review covers some aspects of fetal-maternal microchimerism, including its impact on the course of pregnancy. The existence of fetal micro-chimerism during pregnancy confirms the fact that the maternal immune system interacts with fetal antigens long before delivery. Also, fetal microchimerism may influence the course of auto-immune diseases during pregnancy, which is associated with the fetal-maternal HLA compatibil-ity. Scientists suggest that autoimmune processes that develop after pregnancy are in fact “graft versus host” reactions that occur in response to fetal allogeneic cells. Maternal cells can also cross the placental barrier. This results in the development of tolerance to maternal antigens that are foreign to the fetus. This postnatal immune tolerance is presumably involved in the immuno-suppressive mechanisms that contribute to fetal survival in utero. It has been proven that the fetal immune system is functionally active and is formed in utero due to fetal-maternal microchimerism, non-sterile placental environment under the impact of maternal microbiota and transplacental transfer of immunoglobulins, by inflammatory mediators and cytokines. An important finding is the absence of signs of maternal microchimerism (MMc) in women with preeclampsia. Many questions remain unanswered, therefore, further studies on fetal-maternal microchimerism are needed to assess its impact on the human body. Key words: fetal-maternal microchimerism, immune tolerance, placental barrier, pregnancy, preeclampsia

Fetal microchimerism and implications for maternal health

This review paper outlines the definition, pathophysiology, and potential maternal health consequences of cellular fetal microchimerism, the maternal acquisition of intact cells of fetal origin during pregnancy. Increased rates and amounts of cellular fetal microchimerism are associated with several placental syndromes, including preeclampsia and fetal growth restriction. The discovery of cellular fetal microchimerism and methods of detection are briefly outlined, and we present the mechanisms hypothesized to govern pregnancy-related and long-term maternal health effects of cellular fetal microchimerism. Specifically, we discuss the potential implications of cellular fetal microchimerism in wound healing, autoimmunity, cancer, and possibly cardiovascular disease. Cellular fetal microchimerism represents a novel area of research on maternal and transgenerational health and disease, providing exciting opportunities for developing new disease biomarkers and precision medicine with targeted prophylaxis against long-term maternal disease.

PSI-30 Identification of fetal microchimerism in older ewes using qPCR

The presence of a male co-twin during pregnancy has been found to impact lifetime reproductive performance in the sibling ewe. XY chimerism, thought to originate from a male co-twin, has been observed in ewes, and may be associated with the rare development of freemartins. Fetal ram DNA has been observed in the maternal circulation during pregnancy, but it is unknown if this chimerism persists after parturition. The objective of this study was to determine if fetal male cells were present in soft tissues of older ewes and if so, does the occurrence differ with lifetime offspring sex ratio. Eight ewes approximately 7-years-old and having given birth to at least 71% female (n = 4) or 82% males (n = 4) were tested. DNA was extracted from 10 different tissues from each ewe (n = 80). In triplicate, real-time PCR (qPCR) was used to identify the presence of the SRY gene in each sample. Using the SRY primer pair, male DNA was identified in the brain (between 1.25 ng / µL and 125 pg / µL) and liver (between 125 and 12.5 pg / µL) from a ewe that had given birth to two males during her lifetime. If any additional male fetal DNA was present, it was below the detectable limits. In addition to giving birth to two males, this ewe was also born with two male co-siblings, thus the origin (sibling or offspring) of the male DNA is not known. These data suggest fetal cell transfer in sheep is possible and the frequency of fetal microchimerism is not associated with sex ratio of lifetime offspring.

Assessment of microchimerism following somatic cell nuclear transfer and natural pregnancies in goats

Microchimerism is defined as the presence of a small population of cells or DNA in 1 organism originated from a genetically different organism. It is well established that this phenomenon occurs in humans and mice as cells are exchanged between mother and fetus during gestation. Currently, no information is available about the presence of maternal microchimerism in goats, and the only published study is limited to an evaluation of fetal and fetal–fetal microchimerism in blood samples following natural breeding. In order to determine whether bidirectional fetal–maternal cell or DNA trafficking occurs in goats, we assessed: 1) fetal microchimerism in surrogates that gave birth to somatic cell nuclear transfer (SCNT)-derived transgenic offspring (n = 4), 2) maternal microchimerism following natural breeding of SCNT-derived transgenic does with a nontransgenic buck (n = 4), and 3) fetal–fetal microchimerism in nontransgenic twins of transgenic offspring (n = 3). Neomycin-resistance gene (NEO) gene was selected as the marker to detect the presence of the αMHC-TGF-β1-Neo transgene in kidney, liver, lung, lymph node, and spleen. We found no detectable maternal or fetal–fetal microchimerism in the investigated tissues of nontransgenic offspring. However, fetal microchimerism was detected in lymph node tissue of one of the surrogate dams carrying a SCNT pregnancy. These results indicate occurrence of cell trafficking from fetus to mother during SCNT pregnancies. The findings of this study have direct implications on the use and disposal of nontransgenic surrogates and nontransgenic offspring.