Why is placentation abnormal in preeclampsia? - PubMed (original) (raw)

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Why is placentation abnormal in preeclampsia?

Susan J Fisher. Am J Obstet Gynecol. 2015 Oct.

Abstract

The causes of preeclampsia remain one of the great medical mysteries of our time. This syndrome is thought to occur in 2 stages with abnormal placentation leading to a maternal inflammatory response. Specific regions of the placenta have distinct pathologic features. During normal pregnancy, cytotrophoblasts emigrate from the chorionic villi and invade the uterus, reaching the inner third of the myometrium. This unusual process is made even more exceptional by the fact that the placental cells are hemiallogeneic, coexpressing maternal and paternal genomes. Within the uterine wall, cytotrophoblasts deeply invade the spiral arteries. Cytotrophoblasts migrate up these vessels and replace, in a retrograde fashion, the maternal endothelial lining. They also insert themselves among the smooth muscle cells that form the tunica media. As a result, the spiral arteries attain the physiologic properties that are required to perfuse the placenta adequately. In comparison, invasion of the venous side of the uterine circulation is minimal, sufficient to enable venous return. In preeclampsia, cytotrophoblast invasion of the interstitial uterine compartment is frequently shallow, although not consistently so. In many locations, spiral artery invasion is incomplete. There are many fewer endovascular cytotrophoblasts, and some vessels retain portions of their endothelial lining with relatively intact muscular coats, although others are not modified. Work from our group showed that these defects mirror deficits in the differentiation program that enables cytotrophoblast invasion of the uterine wall. During normal pregnancy, invasion is accompanied by the down-regulation of epithelial-like molecules that are indicative of their ectodermal origin and up-regulation of numerous receptors and ligands that typically are expressed by endothelial or vascular smooth muscle cells. For example, the expression of epithelial-cadherin (the cell-cell adhesion molecule that many ectodermal derivatives use to adhere to one another) becomes nearly undetectable, replaced by vascular-endothelial cadherin, which serves the same purpose in blood vessels. Invading cytotrophoblasts also modulate vascular endothelial growth factor ligands and receptors, at some point in the differentiation process expressing every (mammalian) family member. Molecules in this family play crucial roles in vascular and trophoblast biology, including the prevention of apoptosis. In preeclampsia, this process of vascular mimicry is incomplete, which we theorize hinders the cells interactions with spiral arterioles. What causes these aberrations? Given what is known from animal models and human risk factors, reduced placental perfusion and/or certain disease states (metabolic, immune and cardiovascular) lie upstream. Recent evidence suggests the surprising conclusion that isolation and culture of cytotrophoblasts from the placentas of pregnancies complicated by preeclampsia enables normalization of their gene expression. The affected molecules include SEMA3B, which down-regulates vascular endothelial growth factor signaling through the PI3K/AKT and GSK3 pathways. Thus, some aspects of the aberrant differentiation of cytotrophoblasts within the uterine wall that is observed in situ may be reversible. The next challenge is asking what the instigating causes are. There is added urgency to finding the answers, because these pathways could be valuable therapeutic targets for reversing abnormal placental function in patients.

Keywords: HLA-G; PLGF; angiogenic factor; cytotrophoblast; endoglin; endothelial cell; inflammation; placenta; pregnancy; spiral artery.

Copyright © 2015 Elsevier Inc. All rights reserved.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1

Figure 1

Placental cytotrophoblasts invade the uterine wall where they breach veins and extensively remodel maternal spiral arterioles. The bulk of the placenta is composed of numerous tree-like projections termed chorionic villi where maternal-fetal exchange occurs. These structures mediate the passage of nutrients, gases and wastes between fetal blood, which circulates through the villous core, and maternal blood, which circulates through the intervillous space. The uteroplacental circulation is established by cytotrophoblasts that acquire an invasive/endothelial phenotype as they leave the placenta and enter the uterine wall. Differentiation begins when cytotrophoblast progenitors that reside in a single layer surrounding the stromal core of anchoring villi emigrate, forming a cell column. These structures attach to the uterine wall and give rise to cells that invade the underlying decidual stroma. Invasive cytotrophoblasts breach uterine blood vessels connecting both the arterial and the venous circulation to the intervillous space. However, once this connection is made, remodeling of the venous side is halted. By contrast, cytotrophoblasts migrate up the lumina of spiral arterioles, eventually replacing the endothelial lining of the vessels and part of the muscular wall. This process encompasses the decidual and inner third of the myometrial segments of these vessels. NK, natural killer; mϕ, macrophage. Figure and legend reprinted with permission from Development.

Figure 2

Figure 2

VE-cadherin is not detected on cytotrophoblasts (CTBs) in pre-eclamptic placentas. Sections of age-matched 26-wk control (CON, A–D) and HELLP pre-eclamptic (PE, E–H) tissue double stained for cytokeratin (CK; A, C, E, and G) and VE-cadherin (B, D, F, and H). (A, B) Control anchoring villus and placental bed. VE-cadherin staining is not detected on villous CTBs but is present on CTBs within columns and the uterine wall. (C, D) Section of a maternal spiral artery in control placental bed tissue. VE-cadherin staining is especially strong on intravascular CTBs and CTBs that are associated with the vessel wall. (E, F) Section of preeclamptic anchoring villus and placental bed. VE-cadherin staining is not detected. (G, H) Section through a small blood vessel surrounded by CTBs. VE-cadherin is not detected on vessel-associated CTBs or CTBs within the surrounding tissue. However, the endothelial cells (EC) that line the vessel did stain (arrows). Figure and legend reprinted with permission from Journal of Clinical Investigation.

Figure 3

Figure 3

Severe PE-associated aberrations in cytotrophoblast (CTB) gene expression return to control values after 48 hours of culture. RNA was collected immediately after the cells were isolated (0 hour) and after 12, 24, and 48 hours in culture. The relative gene expression levels for CTBs isolated from gestational age matched placentas of patients who delivered due to severe PE (n = 5) relative to noninfected preterm labor (nPTL) are shown as a heat map. The average fold changes for each time point (severe PE vs. nPTL) are shown. ns, no significant difference (LIMMA). Figure and legend reprinted with permission from Journal of Clinical Investigation. The data are a truncated form of the original heatmap that was published.

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