Oxidatively modified LDL particles in the human placenta in early and late onset intrauterine growth restriction.

INTRODUCTION: Reduced serum LDL concentrations have been observed in pregnancies complicated by intrauterine growth restriction (IUGR) as compared to healthy pregnant women. Since increased oxidative stress has been suggested to play a major role in IUGR we now hypothesized that the lower LDL concentrations are accompanied by an accumulation of oxidized LDLs in the placenta. METHODS: Fifteen placentas of near term and preterm born IUGR, and a gestational age matched control group (CTRL n = 15) were analyzed. Placental minimal modified LDL and fully oxidized LDL particles were measured by ELISA, and by immunohistochemistry, and were related to maternal and fetal serum lipid profiles. RESULTS: We found fully oxidized LDL but not minimal modified LDL being increased in the preterm subgroup of IUGR (n = 10) as compared to preterm CTRL (n = 10; p < 0.05). An increased staining intensity of trophoblasts in preterm IUGR subjects as compared to preterm CTRL has been confirmed by immunohistochemistry (p < 0.05). No difference could be found between the term groups (n = 5 each). Correlation analysis revealed an inverse relationship of maternal LDL (ρ = −0.49, p = 0.03) and fetal HDL cholesterol (ρ = −0.46, p = 0.04) with placental fully oxidized LDL particle concentration within preterms. DISCUSSION: IUGR is a heterogeneous entity. Different pathomechanisms seem to underlie the disease in preterm and term subjects with oxidation of LDL within the placenta possibly taking place in preterm IUGRs. CONCLUSIONS: We conclude that the reduced maternal LDL cholesterol concentration in IUGR pregnancies is attributed to increased accumulation of oxidized LDL particles within the placenta at least in early onset IUGR

[Determination of maternal and foetal serum lipid profile and placental oxidised low density lipoprotein accumulation in preeclampsia and normotensive pregnancies]. / Untersuchungen des maternalen und fetalen Serumlipidprofils und des oxidierten 'Low Density' Lipoproteins im plazentaren Gewebe bei Präeklampsie und normotensiven Schwangerschaften.

BACKGROUND: Oxidised low density lipoproteins (oxLDL) are key players in the development of atherosclerotic cardiovascular diseases. Since there are similarities between the pathogenesis of preeclampsia and atherosclerosis we hypothesised an increased accumulation of oxLDL at the materno-foetal and foeto-foetal interface within the placental tissue of preeclamptic women compared to women with normotensive pregnancies (controls). Moreover, we analysed maternal and foetal serum lipid parameters. PATIENTS AND METHODS: oxLDL was determined by immunohistochemistry in placental paraffin sections of 14 women suffering from preeclampsia (30th-39th week of gestation) and compared to 28 preterm and term deliveries (25th-40th week of gestation). 10 high power fields were chosen randomly by the newCAST software and oxLDL expression was analysed via standardised methods by 2 independent and blinded investigators. Maternal and foetal triglycerides, total cholesterol, LDL cholesterol and HDL cholesterol were measured. Statistical examination was carried out by the Mann-Whitney test. RESULTS: oxLDL was found in villous trophoblast and placental endothelium. No significant differences were observed in expression intensity between preeclampsia and controls. Maternal and foetal triglyceride levels were significantly increased in preeclampsia compared to controls (pre-eclampsia mothers: 293 [SD 87.4] mg/dL, controls: 214 [SD 89.4] mg/dL, p=0.0097; preeclampsia foetuses: 26 [SD 16.6] mg/dL, controls: 18 [SD 10.4] mg/dL, p=0.0463). No significant differences in other lipid concentrations were found. CONCLUSIONS: We could not confirm our initial hypothesis of an increased oxLDL accumulation in placental tissue of preeclampsia. However, preeclampsia is a condition of dyslipidaemia affecting both maternal and foetal serum with implications for development and programming of cardiovascular diseases in later life.

PP013. Oxidized low density lipoprotein accumulation and the expression of the lectin-like oxLDL receptor (LOX-1) in placental tissue in preeclampsia and healthy controls.

INTRODUCTION: Oxidized Low Density Lipoproteins (oxLDL) and its receptor the lectin-like oxLDL receptor 1 (LOX-1) are key players in the development of atherosclerotic cardiovascular diseases. OBJECTIVES: Since preeclampsia is known to share similarities to the pathogenesis of atherosclerosis we hypothesized an increased accumulation of oxLDL and an increased expression of LOX-1 at the materno-fetal and feto-fetal interface within the placental tissue in preeclampsia in comparison to a control group. Second, we analyzed maternal and fetal serum lipid parameters including fetal oxLDL concentration. METHODS: OxLDL and LOX-1 intensity was determined via immunohistochemistry in placental paraffin sections of 11 women suffering from preeclampsia and compared to 11 gestational age matched preterm deliveries (29th to 36th week of gestation). Ten 'High Power Fields' were chosen randomly by the newCAST software and expression was analyzed via standardized methods by two independent and blinded observers. Maternal and fetal triglycerides, total cholesterol, LDL-cholesterol and HDL-cholesterol were measured by enzymatic colorimetric methods. Fetal oxLDL serum concentration was estimated by ELISA. Statistical examination was carried out by Student's t-test. Skewed variables were log-transformed. RESULTS: oxLDL and LOX-1 was predominantly found to be in villous trophoblast and placental endothelium. No significant differences could be observed in oxLDL expression intensities between preeclampsia and controls. LOX-1 expression tended to be increased in placental trophoblast and endothelium without being statistical significant (Table 1). Fetal triglyceride levels were significantly elevated in preeclampsia compared to controls while maternal triglyceride levels tend to be increased. No other significant differences in lipid concentrations could be observed (Table 2). CONCLUSION: We could not confirm our initial hypothesis of an accelerated oxLDL accumulation in placental tissue of preeclampsia. Though not statistically significant, placental endothelium seems to be activated in preeclampsia since LOX-1 expression is increased. Moreover, preeclampsia is a condition of dyslipidemia affecting both, maternal and fetal serum with implications for development of cardiovascular diseases in later life.

PP014. Estimating fully and minimal oxidized low density lipoprotein accumulation in placental tissue in intrauterine growth restriction and healthy controls.

INTRODUCTION: We recently demonstrated that maternal serum LDL- and fetal serum HDL-cholesterol concentration is significantly reduced in intrauterine growth restriction (IUGR) [1]. OBJECTIVES: We now hypothesized that increased oxidative stress in IUGR placenta leads to an accumulation of oxidized LDL (oxLDL) particles which then become trapped within the placenta subsequently leading to reduced availability of cholesterol for mother and fetus. METHODS: Fully oxidized LDL (oxLDL) was determined via immunohistochemistry in placental paraffin sections of 18 women suffering from IUGR and 18 gestational age matched controls. Ten 'High Power Fields' were chosen randomly by the newCAST software and oxLDL expression was estimated via standardized methods by two independent and blinded observers. Minimal oxidatively modified LDL (MM-LDL) and non-modified Apolipoprotein B (ApoB) concentration was measured in full placental tissue lysates by ELISA. Values were correlated with maternal and fetal total cholesterol, LDL-, and HDL-cholesterol concentrations. Statistical examinations were carried out by Student's t-test and calculation of Pearson's correlation coefficient. RESULTS: oxLDL was found predominantly to be in villous trophoblast and placental endothelium. OxLDL intensity tended to be increased in IUGR (Table 1). We found MM-LDL concentrations in whole placental tissue lysates to be highly correlated to placental ApoB concentration (r=0.93). Both parameters were non-significantly decreased in placenta of IUGR compared to controls (Table 1). Maternal serum LDL-C, and fetal serum LDL-C, TC, and HDL-C concentrations were significantly decreased in IUGR compared to controls (Table 2). OxLDL staining intensity was mildly negatively correlated to maternal LDL-C (r=-0.315) and much less to fetal HDL-C concentrations (r=-0.212). Placental ApoB and MM-LDL concentration were moderately positively correlated with fetal HDL-C concentrations (r=0.492 and r=0.447). CONCLUSION: Conformational changes of the ApoB lipoprotein during the process of oxidation might lead to an accumulation of oxLDL particles in placental tissue of IUGR and reduced fetal cholesterol bioavailability as evidenced by a decrease in fetal serum cholesterol levels. However, our analysis lacks in sufficient power and further studies are underway focussing on that subject.