Why is placentation abnormal in preeclampsia?

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.

Fisher SJ 《-》

Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome.

Zhou Y ，McMaster M ，Woo K ，Janatpour M ，Perry J ，Karpanen T ，Alitalo K ，Damsky C ，Fisher SJ ... -  《-》

TGFβ signalling: a nexus between inflammation, placental health and preeclampsia throughout pregnancy.

Horvat Mercnik M ，Schliefsteiner C ，Sanchez-Duffhues G ，Wadsack C ... -  《-》

Up-regulation of CD81 inhibits cytotrophoblast invasion and mediates maternal endothelial cell dysfunction in preeclampsia.

Shen L ，Diao Z ，Sun HX ，Yan GJ ，Wang Z ，Li RT ，Dai Y ，Wang J ，Li J ，Ding H ，Zhao G ，Zheng M ，Xue P ，Liu M ，Zhou Y ，Hu Y ... -  《-》

Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia.

Physiological transformation with remodeling of the uteroplacental spiral arteries is key to a successful placentation and normal placental function. It is an intricate process that involves, but is not restricted to, complex interactions between maternal decidual immune cells and invasive trophoblasts in the uterine wall. In normal pregnancy, the smooth muscle cells of the arterial tunica media of uteroplacental spiral arteries are replaced by invading trophoblasts and fibrinoid, and the arterial diameter increases 5- to 10-fold. Poor remodeling of the uteroplacental spiral arteries is linked to early-onset preeclampsia and several other major obstetrical syndromes, including fetal growth restriction, placental abruption, and spontaneous preterm premature rupture of membranes. Extravillous endoglandular and endovenous trophoblast invasions have recently been put forth as potential contributors to these syndromes as well. The well-acknowledged disturbed extravillous invasion of maternal spiral arteries in preeclampsia is summarized, as are briefly novel concepts of disturbed extravillous endoglandular and endovenous trophoblast invasions. Acute atherosis is a foam cell lesion of the uteroplacental spiral arteries associated with poor remodeling. It shares some morphologic features with early stages of atherosclerosis, but several molecular differences between these lesions have also recently been revealed. Acute atherosis is most prevalent at the maternal-fetal interface, at the tip of the spiral arteries. The localization of acute atherosis downstream of poorly remodeled arteries suggests that alterations in blood flow may trigger inflammation and foam cell development. Acute atherosis within the decidua basalis is not, however, confined to unremodeled areas of spiral arteries or to hypertensive disorders of pregnancy and may even be present in some clinically uneventful pregnancies. Given that foam cells of atherosclerotic lesions are known to arise from smooth muscle cells or macrophages activated by multiple types of inflammatory stimulation, we have proposed that multiple forms of decidual vascular inflammation may cause acute atherosis, with or without poor remodeling and/or preeclampsia. Furthermore, we propose that acute atherosis may develop at different gestational ages, depending on the type and degree of the inflammatory insult. This review summarizes the current knowledge of spiral artery remodeling defects and acute atherosis in preeclampsia. Some controversies will be presented, including endovascular and interstitial trophoblast invasion depths, the concept of 2-stage trophoblast invasion, and whether the replacement of maternal spiral artery endothelium by fetal endovascular trophoblasts is permanent. We will discuss the role of acute atherosis in the pathophysiology of preeclampsia and short- and long-term health correlates. Finally, we suggest future opportunities for research on this intriguing uteroplacental interface between the mother and fetus.

Staff AC ，Fjeldstad HE ，Fosheim IK ，Moe K ，Turowski G ，Johnsen GM ，Alnaes-Katjavivi P ，Sugulle M ... -  《-》