Stereological study of the effect of altitude on the trophoblast cell populations of human term placental villi

doi:10.1016/S0143-4004(97)80046-X

Placenta

Volume 18, Issues 5–6, 1997, Pages 447-450

https://doi.org/10.1016/S0143-4004(97)80046-X Get rights and content

Paraffin-embedded histological material was examined from 10 placentae from uncomplicated pregnancies at high altitude (3000 m). This was compared with material from 10 placentae delivered at low altitude (500 m). The sample groups were matched for maternal age, gestational age and parity. Within terminal and intermediate villi the volume-weighted mean cytotrophoblast cell volume did not significantly change at high altitude (754.1 μm³ at low altitude versus 796 μm³ at high altitude). The fractional volume of the villi occupied by cytotrophoblastic cells and their nuclei number per 10 000 μm³ of villous tissue were significantly greater in placenta from high altitude (3.17 and 1.86 per cent, respectively) than those from low altitude (1.05 and 0.79 per cent, respectively) (P<0.0004 and P<0.0058, respectively). No significant differences in either fractional volume of the syncytiotrophoblast or its nuclei number per 10 000 μm³ of villous tissue were observed between placentae from high (26.01 and 11.6 per cent, respectively) and low altitude (26.33 and 11.89 per cent, respectively). These results suggest an increase in the number of cytotrophoblastic cells at high altitudes without any changes in their volume. Exposure to hypobaric hypoxia is thought to be the principal aetiological factor.

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Cited by (29)

Hypoxic switch in mitochondrial myeloid cell leukemia factor-1/Mtd apoptotic rheostat contributes to human trophoblast cell death in preeclampsia
2007, American Journal of Pathology
Citation Excerpt :
Normal physiological regulation of trophoblast cell fusion utilizes a molecular apoptotic cascade in which mononucleated cytotrophoblast cells fuse to maintain a multinucleated syncytiotrophoblast cell layer.58 Normal SL term placentae have a well-defined syncytiotrophoblast layer, which is in contrast to HA placentae, which show thinning of the syncytiotrophoblast layer and a hyperproliferative cytotrophoblast phenotype59 suggesting decreased syncytial renewal under conditions of reduced oxygenation.56,60,61 Decreased expression of active caspase-8, a promoter of trophoblast cell fusion,62 in conjunction with reduction of other cell death markers in HA placentae, as demonstrated by decreased cleaved p85 PARP formation, suggests a slowdown of syncytial formation and consequently trophoblast shedding during chronic placental hypoxia.
Preeclampsia, a disorder of pregnancy, is characterized by increased trophoblast cell death and altered trophoblast-mediated remodeling of myometrial spiral arteries resulting in reduced uteroplacental perfusion. Mitochondria-associated Bcl-2 family members are important regulators of programed cell death. The mechanism whereby hypoxia alters the mitochondrial apoptotic rheostat is essential to our understanding of placental disease. Herein, myeloid cell leukemia factor-1 (Mcl-1) isoform expression was examined in physiological/pathological models of placental hypoxia. Preeclamptic placentae were characterized by caspase-dependent cleavage of death-suppressing Mcl-1L and switch toward cell death-inducing Mcl-1S. In vitro, Mcl-1L cleavage was induced by hypoxia-reoxygenation in villous explants, whereas Mcl-1L overexpression under hypoxia-reoxygenation rescued trophoblast cells from undergoing apoptosis. Cleavage was mediated by caspase-3/-7 because pharmacological caspase inhibition prevented this process. Altitude-induced chronic hypoxia was characterized by expression of Mcl-1L; resulting in a reduction of apoptotic markers (cleaved caspase-3/-8 and p85 poly-ADP-ribose polymerase). Moreover, in both physiological (explants and high altitude) and pathological (preeclampsia) placental hypoxia, decreased trophoblast syncytin expression was observed. Hence, although both pathological and physiological placental hypoxia are associated with slowed trophoblast differentiation, trophoblast apoptosis is only up-regulated in preeclampsia, because of a hypoxia-reoxygenation-induced switch in generation of proapoptotic Mcl-1 isoforms.
Human placental hypoxia-inducible factor-1α expression correlates with clinical outcomes in chronic hypoxia in vivo
2007, American Journal of Pathology
Citation Excerpt :
The observation that VHL expression is elevated in conditions of chronic hypoxia is in agreement with our recent observation showing increased VHL in early gestation20 and with other in vitro studies showing oxygen-dependent changes in VHL expression both in cell lines and villous explants.47,48 In addition, the elevated level of VHL may contribute to other features noted in the high-altitude placenta, eg, cytotrophoblast proliferation,49 because VHL plays a role in regulating a variety of cellular events including cell proliferation and extracellular matrix assembly.50,51 The finding of less neddylated CUL2 in HA placentas is also consistent with the prior literature.
Placental hypoxia is causally implicated in fetal growth restriction and preeclampsia, with both occurring more frequently at high altitude (>2700 m; HA). The nuclear transcription factor hypoxia-inducible factor (HIF) may facilitate placental oxygen transport at HA by increasing erythropoiesis and placental angiogenesis. We therefore investigated HIF expression and its regulatory mechanisms in placentas from normal pregnancies at high (3100 m), moderate (1600 m), and sea level (75 m) altitudes. Moderate-altitude and sea level placentas did not differ, but HIF-1α and the von Hippel-Lindau tumor suppressor protein were overexpressed in HA placentas. The ability of von Hippel-Lindau tumor suppressor protein to form the E3 ubiquitin protein ligase complex, required for HIF-1α degradation, was unaltered in HA placentas. mRNA for factor-inhibiting HIF, a negative modulator of HIF-1α transactivation, was increased, but protein levels were diminished. Elevated HIF-1α likely contributed to the significant increase we report in HIF-1α downstream target proteins, transforming growth factor β3 in the placenta, and vascular endothelial growth factor and erythropoietin in the maternal circulation. These circulating markers and lowered birth to placental weight ratios correlated with increased HIF-1α, thereby linking molecular and systemic physiological data. The HA response to chronic hypoxia resembles preeclampsia in several aspects, illustrating the utility of the HA model in understanding placental pathologies.
Histomorphometric characterisation of shared and non-shared cotyledonary villus territories of monochorionic placentae in relation to pregnancy complications
2006, Placenta
Citation Excerpt :
Placental vascular anatomy has been linearly linked to placental discordance and birthweight discordance [1]. Chorionic villi have been studied extensively in singleton placentas in relation to high altitude [10–14] and umbilical artery Doppler flow [15–19]. It is now generally accepted that reduced end-diastolic frequencies in the umbilical artery in singleton pregnancies with IUGR are associated with changes in terminal villi including reduced villus diameter, reduced degree of vascularization, larger fetomaternal diffusion distance and smaller capillaries [15,16,20].
Theoretical estimates and physiological inferences suggest that the structure of a shared cotyledon differs from a non-shared cotyledon. The aim of this study was to characterise the histomorphometry of terminal villi in shared and non-shared cotyledons in monochorionic placentae, both from uncomplicated twins and from those with twin–twin transfusion syndrome (TTTS) or discordant growth restriction (ΔIUGR).
Forty-one monochorionic placentae from Caucasian non-smokers were obtained at caesarean section. Their vascular anatomy and placental territories were ascertained by dye injection. After fixation, full thickness histological blocks were obtained by systematic random sampling from each twin's territory and the shared cotyledons. Fifty randomly selected terminal villi were assessed for: (i) median villus diameter (ii) median villus capillary diameter (iii) median fetomaternal diffusion distance (iv) median no. of capillaries/villus (v) degree of vascularization (median percentage cross-sectional area of terminal villi occupied by capillaries) using a stage micrometer and image analysis programme. The histomorphometric findings were then correlated with birthweight discordance, placental territory discordance and ΔAVAs (no. of AVAs from smaller twin (donor) to larger twin (recipient) minus no. of AVAs from larger to smaller twin).
Histomorphometric variables were similar in shared and non-shared cotyledons of uncomplicated MCDA twins. However, the median diameter of terminal villi in shared cotyledons in ΔIUGR and TTTS placentae was significantly smaller [51.2 μm (48.2–58.3), p < 0.001 and 52.6 μm (53.1–50.4), p < 0.001], and had a similar number of smaller capillaries, larger fetomaternal diffusion distance and reduced vascularization compared to non-shared IUGR and TTTS placentae. However, Δdiameter (defined as the difference between median diameters of terminal villi in large minus small twins' territories) rose with increasing birthweight discordance (Pearson correlation coefficient = 0.82, p < 0.001). Multiple linear regression analysis revealed that Δdiameter was influenced by placental territory discordance (p < 0.001) and birthweight discordance (p < 0.01): log₁₀ Δdiameter = 1.38 + (0.01 × birthweight discordance) + (0.56 × log₁₀ placental territory discordance) (R² = 0.82, p < 0.001), but there was no significant relationship with ΔAVA and AAA. In the TTTS group, Δdiameter correlated significantly with ΔAVA only: log₁₀ Δdiameter = 1.44 + (0.02 × ΔAVA) (R² = 0.3, p < 0.001).
This is the first study to characterise the histomorphometry of shared and non-shared cotyledons in MC twins. The findings suggest that abnormal placentation, rather than placental vascular anatomy may be responsible for ΔIUGR in MC twins, whereas TTTS arises from imbalance in interfetal transfusion with resultant differing terminal villus histomorphometric features in donor, recipient and shared cotyledons.
Anatomy and genesis of the placenta
2006, Knobil and Neill's Physiology of Reproduction
Fetal cells and cell free fetal nucleic acids in maternal blood: New tools to study abnormal placentation?
2005, Placenta
Citation Excerpt :
Respective changes of the placental morphology have recently been reviewed [93], although comparisons between studies are difficult due to different altitudinal levels, ethnic groups and numbers of cases. It is generally agreed that the terminal villi display increased vascularization, thinning of the syncytiotrophoblast and increased numbers of cytotrophoblast cells [94–97]. It is tempting to assume that these changes represent a compensatory adaptation to facilitate a sufficient oxygen transfer to the fetus, since there is no conclusive evidence that the fetus is hypoxic at high altitude [93].
The analysis of fetal cells, and more recently cell free fetal nucleic acids, in maternal blood has to date largely been concerned with the development of risk free methods for prenatal diagnosis. Although elevated feto-maternal cell trafficking has long been associated with preeclampsia, it has only recently been shown that this perturbation is an early event in these pregnancies, occurring well in advance of the onset of symptoms. In a separate development, analogous observations have been made concerning the levels of circulatory fetal nucleic acids in maternal plasma. Subsequent studies have shown that changes in these two parameters may also occur in other pregnancy related disorders including preterm labour, intra-uterine growth retardation, hyperemesis gravidarum or even pregnancies at high altitude.
A striking finding of these examinations was that preterm labour was associated with an elevated release of cell free fetal nucleic acids but not with an increment in feto-maternal cell trafficking. This suggested that the analysis of the mechanisms regulating trans-placental cell trafficking or liberation of circulatory fetal nucleic acids may provide key insights into the fundamentally different placental lesions underlying these disorders. As such, circulatory fetal cells and nucleic acids may be viewed as new tools to study alterations in placentation.
Anatomy and Genesis of the Placenta
2005, Knobil and Neill's Physiology of Reproduction

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Stereological study of the effect of altitude on the trophoblast cell populations of human term placental villi

American Journal of Obstetrics

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American Journal of Obstetrics and Gynecology

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American Journal of Pathology

Measurement of the villous surface in normal and pathologic placentas

American Journal of Obstetrics and Gynecology