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Menstruation is widely viewed as serving no purpose other than to reinitiate the endometrial cycle in the absence of pregnancy. Yet, it is striking that cyclic endometrial decidualization followed by menstrual shedding is confined to the few species, including human beings, where placenta formation entails deep trophoblast invasion of maternal tissues and its vasculature. Both menstruation and pregnancy are inflammatory conditions that cause a degree of physiological ischemia-reperfusion tissue injury, albeit much more so in pregnancy. Thus, the emergence of cyclic menstruation may not have been an evolutionary coincidence but serves to protect uterine tissues from the profound hyperinflammation and oxidative stress associated with deep placentation, a process known as preconditioning. The concept of menstrual preconditioning provides a novel paradigm for understanding how reproductive disorders impact on pregnancy outcome. For example, endometriosis could be viewed as a disorder of exaggerated menstrual preconditioning that confers protection against placentation-related disorders, such as preeclampsia.

The much publicized conflict hypothesis for understanding fetal-maternal interaction during pregnancy often invokes a 'battle' metaphor, rather than a well orchestrated interplay occurring as a series of well controlled moves and counter-moves as happens in a game of chess. Such stepwise interaction is particularly obvious in the spiral artery remodelling process, and it would be interesting to trace the history of the successive steps in histological adaptation throughout primate phylogeny. The restricted invasion observed in a few species on a 'lower' evolutionary scale suggests a tendency of progressive deeper invasion during primate evolution. Unfortunately, our knowledge of invasive processes in the placental bed in nonhuman primates is highly inadequate. A paradigm underscoring the stepwise interaction between mother and fetus may be provided by the Red Queen hypothesis, which is a useful model to explain co-evolutionary processes between different species. The apparent association between preeclampsia and restricted endovascular trophoblast invasion, combined with the absence of the disease in primate species showing shallow invasion, suggests that preeclampsia may result from a failure in one or more interactive steps necessary for deeper invasion. Evidence for a genetic component invokes the puzzling question as to why "preeclampsia genes" are not eliminated from human populations. As in other fields of medicine, a proper understanding of Darwinian selection processes may throw some light on the causes of preeclampsia.

Deep placentation in the human requires physiologic transformation of the spiral arteries into uteroplacental vessels. This process involves the inner myometrial segment (junctional zone) of the spiral arteries and is effected by trophoblast invasion of the vessel wall, resulting in complete loss of the arterial structure and deposition of fibrinoid and fibrous tissues. Absent or inadequate physiologic changes in the junctional zone spiral arteries limits placental blood flow in pregnancies complicated by preeclampsia and fetal growth restriction. The cause of defective deep placentation is still unknown, although it is often attributed to impaired trophoblast function and migration. However, trophoblast invasion is preceded by decidual remodeling of maternal tissues, a process that is initiated in the endometrium but extends into the junctional zone. This review examines the mechanisms that control decidualization and subsequent trophoblast invasion in normal and abnormal pregnancies. The possibility that disruption of the decidual process in the secretory phase of the menstrual cycle triggers a cascade of events resulting in failed deep placentation is explored.

Abstract: Since the earliest report on impaired spiral artery remodelling in preeclamptic human pregnancies, numerous studies have been devoted to possible mechanisms of impaired trophoblast invasion. A better knowledge of early uteroplacental blood flow has provided a physiological context for the processes of spiral artery invasion and associated remodelling, revealing a closely timed relationship between increasing flow and early steps in vascular remodelling. Concerning the impaired trophoblast invasion in preeclampsia, it has also to be considered that impaired invasion not only concerns invasion depth per se, but also the extension of this deep invasion from the central towards the more lateral spiral arteries of the placental bed. Since also in preeclampsia the very central spiral arteries may be normally invaded, the existence of such spatial gradient provides a further dimension to the problem. A practical consequence is that frequently used rodent models, which show invasion of two or three spiral arteries only, may be less useful for studying this particular aspect of the disease. Amongst non-human primates, baboons and rhesus monkeys are ‘shallow invaders’, and only in some of the great apes deep trophoblast invasion and associated spiral artery remodelling occurs. A better knowledge of the evolutionary history of deep invasion and its possible selective benefit might ultimately improve our understanding of failed deep invasion and impaired spiral artery remodelling in preeclampsia. [ABSTRACT FROM AUTHOR]

Rats harboring the human angiotensinogen and human renin genes develop preeclamptic features in pregnancy. The preeclamptic rats exhibit a deeper trophoblast invasion associated with a reduced resistance index by uterine Doppler. Doxycycline inhibits matrix metalloproteinase activity. We tested the hypothesis that matrix metalloproteinase inhibition reduces trophoblast invasion with subsequent changes in placental perfusion. Preeclamptic and pregnant control Sprague-Dawley rats were treated with doxycycline (30 mg/kg of body weight orally) from gestational day 12 until day 18. Placental perfusion was assessed using a micromarker contrast agent. The animals were euthanized on day 18 of pregnancy; biometric data were acquired, and trophoblast invasion was analyzed. Doxycycline resulted in intrauterine growth retardation and lighter placentas in both groups. Maternal body weight was not affected. As shown earlier, preeclamptic rats exhibited a deeper endovascular trophoblast invasion. However, doxycycline treatment reduced trophoblast invasion in the preeclamptic rats. The physiological spiral artery remodeling, as assessed by the deposition of fibrinoid and alpha-actin in the spiral artery contour, was significantly reduced by doxycycline. The vascularity index, as assessed by perfusion measurement of the placenta, was reduced after doxycycline treatment in preeclamptic rats. Thus, matrix metalloproteinase inhibition with doxycycline leads to reduced trophoblast invasion and associated reduced placental perfusion. These studies are the first to show that reducing trophoblast-induced vascular remodeling decreases subsequent placental perfusion. Our model allows the study of dysregulated trophoblast invasion and vascular remodeling in vivo to gain important insights into preeclampsia-related mechanisms. [ABSTRACT FROM AUTHOR]

While there is a growing realization that the origins of major obstetrical complications associated with defective deep placentation, such as pre-term labour, fetal growth restriction and pre-eclampsia, may lie in the very early pregnancy events, the underlying mechanisms are not understood. Impaired deep placentation is foremost a vascular pathology, characterized by a lack of endovascular trophoblast invasion and remodelling of a segment of the spiral arteries embedded within the inner myometrium of the uterus. Outside pregnancy, the inner myometrium represents a highly specialized, hormone-dependent structure, termed the junctional zone (JZ), which plays an integral part in the implantation process. The JZ changes with age and is disrupted in several reproductive disorders, such as endometriosis and adenomyosis, which in turn may account for the increased risk of adverse pregnancy outcome. Unlike the endometrium, the myometrial JZ is not readily accessible to biochemical or molecular studies, yet its structure and function can be assessed using imaging techniques, such as high-resolution ultrasound and magnetic resonance imaging. Thus, non-invasive assessment of the JZ prior to conception may turn out to be useful in identifying those women at risk of major obstetrical complications. [ABSTRACT FROM PUBLISHER]