Who Let the Dogs In: A Canine Trophoblast Invasion Model for Pre‐eclampsia

Abstract

ContentsPre-eclampsia affects 2-8% of pregnant women worldwide and is the third leading cause of maternal mortality in the United States, accounting for 20% of maternal deaths, for which the only known cure is delivery of the placenta. It is known that pre-eclampsia results from defects within the trophoblast invasion of the endometrium and myometrium. At a morphological level within the pre-eclamptic human placenta, trophoblast invasion is shallow, and this results in hypoperfusion, which is a life-threatening condition for both the mother and the foetus. Pre-eclampsia has been intensively investigated for over 50 years, and yet the causes are largely unknown. Despite a large body of data, it is still unknown exactly which mechanisms regulate trophoblast invasion. An effective animal model may be crucial to understanding the underlying causes of pre-eclampsia. A canine model is a proposed improvement on the current efforts to investigate disorders of shallow trophoblast invasion throughout gestation and to improve understanding of the factors that regulate trophoblast invasion. The objectives of this research were to elucidate and compare cellular and molecular similarities between normal canine trophoblasts with those from recently published reports on pre-eclampsia in women.

Placental Evolution within the Supraordinal Clades of Eutheria with the Perspective of Alternative Animal Models for Human Placentation

“…In humans, this disease results from shallow trophoblast invasion into the endometrium and myometrium, followed life-threatening conditions for both the mother and the fetus. Since the dog has shallow trophoblast invasion throughout gestation, it may improve the understanding of the underlying reasons and exact mechanisms for pre-eclampsia [164]. Data show that the shallow trophoblast invasion in the endotheliochorial placentation of dogs is mainly regulated by matrix metalloproteinases, similar to what is known from humans [165].…”

“…Finally, there are recent studies on preeclampsia in the dog model [164,165]. In humans, this disease results from shallow trophoblast invasion into the endometrium and myometrium, followed life-threatening conditions for both the mother and the fetus.…”

Comparative matrix metalloproteinase-2 and -9 expression and activity during endotheliochorial and hemochorial trophoblastic invasiveness

“…For this reason, it is important to search for models with larger body size that deliver more developed offspring (Carter, 2020). Although both hemochorial and endotheliochorial trophoblast invasion induces transformation of the endometrium, the placenta of Canis familiaris has a higher degree of invasiveness than other endotheliochorial placenta, and therefore has been proposed as a model to study some aspects of human pre-eclampsia (Kutzler et al, 2012). On the other hand, subinvolution of placentation sites is a disorder that produces late postpartum uterine bleeding, among other obstetric complications, during the puerperium of women (Weydert and Benda 2006).…”

Differential expression and activity of matrix metalloproteinases 2 and 9 in canine early placenta

“…In humans, a decline in the production of MMP‐2 and MMP‐9 was associated with growth retardation (Merchant et al., ). On the other hand, some authors (Kutzler et al., ) have argued that the canine placenta could serve as a model for study of human pre‐eclampsia, considering the high invasive capacity of its cells, the fundamental role of MMPs for invasiveness and the altered expression of these enzymes during pre‐eclampsia (Wang et al., ). Given the importance of the metalloprotease expression and activation, specific tissue and gestational period, it is necessary to perform further studies to establish the location, MMPs expression and activity of canine placenta throughout pregnancy.…”

“…Moreover, Kutzler et al. found activity of both enzymes in cultured canine TB cells of term placenta (Kutzler, Sahlfeld, & Fellows, ).…”