Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR

Abstract

Human placental villi are surfaced by an outer multinucleated syncytiotrophoblast and underlying mononucleated cytotrophoblasts. Conflicting data have attributed one, or the other, of these villous trophoblast phenotypes to undergo enhanced apoptosis in complicated pregnancies, compared to term, normotensive pregnancies. We use high-resolution confocal microscopy after co-staining for E-cadherin, as a trophoblast plasma membrane marker, and for the cleavage products of cytokeratin 18 and PARP1, as markers for caspase-mediated apoptosis, to distinguish between apoptotic cytotrophoblasts and apoptosis within the syncytiotrophoblast. We test the hypothesis that increased caspase-mediated apoptosis occurs in villi of placentas derived from pregnancies complicated by preeclampsia, intrauterine growth restriction (IUGR), or both. We find significantly elevated apoptosis in villous cytotrophoblasts from women with preeclampsia and/or IUGR, compared to term, normotensive pregnancies. Apoptosis of cytotrophoblasts in villi from complicated pregnancies appears to progress similarly to what we found previously for apoptotic cytotrophoblasts in villi from in term, normotensive pregnancies. Notably, caspase-mediated apoptosis was not detectable in regions with intact syncytiotrophoblast, suggesting strong repression of apoptosis in this trophoblast phenotype in vivo. We suggest that the elevated apoptosis in cytotrophoblasts in preeclampsia contributes to the placental dysfunction characteristic of this disorder. We also propose that repression of apoptosis in the syncytiotrophoblast is important to prevent apoptosis sweeping throughout the syncytium, which would result in widespread death of this essential interface for maternal-fetal exchange.

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

“…These results suggested that EVTB in early preeclamptic placentas might have higher levels of cell death. This conclusion is in line with previous reports that trophoblastic apoptosis is increased in PE (52)(53)(54)(55)(56)(57)(58)(59). Despite the invasion insufficiency of EVTB in PE, the increased cell death in EVTB may also contribute to the up-regulation of the EVTB signatures in the maternal plasma of early preeclamptic patients.…”

Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia

“…Hence, in PE, oxidative stress favors CER accumulation thereby contributing to the increased placental cell death found in this disease. 17,18,27 Sphingolipid accumulation due to genetic alterations in their regulatory enzymes characterizes various lysosomal sphingolipid storage disorders in humans, including Niemann-Pick 28 and Farber diseases. 9 Our finding of reduced ASAH1 transcription in conjunction with CER accumulation in lysosomes from PE placentae identifies preeclampsia as a new sphingolipid storage disorder, which results from the oxidative stress milieu typical of this pathology.…”

Comparative Proteomic Profile of the Human Placenta in Normal and Fetal Growth Restriction Subjects

“…It is the main cause of intrauterine fetal death and the second leading cause of death in the neonatal period [2]. Although the primary mechanism of FGR is still unknown, a considerable body of evidence suggests that FGR could be associated with many factors such as impaired placental function, inadequate trophoblast invasion, deficient spiral arterial remodeling, and increased apoptosis of trophoblastic cells [3,4,5,6]. Notably, recent studies have indicated that impaired placental function may hold the key to the etiology of FGR [3,7].…”