Increased maternal and fetal cholesterol efflux capacity and placental CYP27A1 expression in preeclampsia

Abstract

Preeclampsia is a pregnancy-specific condition that leads to increased cardiovascular risk in later life. A decrease in cholesterol efflux capacity is linked to CVD. We hypothesized that in preeclampsia there would be a disruption of maternal/fetal plasma to efflux cholesterol, as well as differences in the concentrations of both placental sterol 27-hydroxylase (CYP27A1) and apoA1 binding protein (AIBP). Total, HDL-, and ABCA1-mediated cholesterol effluxes were performed with maternal and fetal plasma from women with preeclampsia and normotensive controls (both n = 17). apoA1 and apoE were quantified by chemiluminescence, and 27-hydroxycholesterol (27-OHC) by GC-MS. Immunohistochemistry was used to determine placental expression/localization of CYP27A1, AIBP, apoA1, apoE, and SRB1. Maternal and fetal total and HDL-mediated cholesterol efflux capacities were increased in preeclampsia (by 10-20%), but ABCA1-mediated efflux was decreased (by 20-35%; P < 0.05). Maternal and fetal apoE concentrations were higher in preeclampsia. Fetal plasma 27-OHC levels were decreased in preeclamptic samples (P < 0.05). Placental protein expression of both CYP27A1 and AIBP were localized around fetal vessels and significantly increased in preeclampsia (P = 0.04). Placental 27-OHC concentrations were also raised in preeclampsia (P < 0.05). Increased HDL-mediated cholesterol efflux capacity and placental CYP27A1/27-OHC could be a rescue mechanism in preeclampsia, to remove cholesterol from cells to limit lipid peroxidation and increase placental angiogenesis.

Keywords: 27-hydroxycholesterol; apolipoproteins; hypertension; lipid/efflux; pregnancy; sterol 27-hydroxylase.

Fig. 1.

Cholesterol efflux with maternal and fetal plasma. A: Cholesterol efflux capacity (percent). B: HDL-mediated (PEG treated) cholesterol efflux (percent). C: ABCA1-mediated cholesterol efflux from normotensive controls (NC) and preeclamptic (PE) plasma. Data are represented as median [IQR]; *P < 0.05; **P < 0.001; ***P < 0.0001.

Fig. 2.

Cholesterol efflux capacity and apoE in PE with AGA or SGA. Maternal (A) and fetal (B) cholesterol efflux was quantified in preeclamptic pregnancies from AGA (n = 11) and SGA (n = 6). apoE was quantified in maternal (C) and fetal (D) plasma from preeclamptic pregnancies with and without SGA. Data are represented as median [IQR]; *P < 0.05.

Fig. 3.

Quantification of 27-OHC in maternal plasma (A), fetal plasma (B), and placental tissue (C). The 27-OHC concentrations were quantified by GC-MS in plasma from normotensive controls (NC) and preeclamptics (PE). In the graphs data are represented as mean ± SD; *P < 0.05.

Fig. 4.

Localization and quantification of placental CYP27A1 immunostaining in placentae from normotensive controls (NC; n = 17) (A), preeclampsia (PE; n = 17) (B), and negative control (C). In photomicrographs, positive cells appear in brown; magnification ×400. Protein expression was localized to Hofbauer cells (black arrows) and fetal vessels (red arrows). In the graph (D), data are represented as mean ± SD; *P < 0.05.

Fig. 5.

Localization and quantification of placental AIBP immunostaining in placentae from normotensive controls (NC; n = 17) (A), preeclampsia (PE; n = 17) (B), and negative control (C). In photomicrographs, positive cells appear in brown; magnification ×400. Protein expression was localized to fetal vessels (red arrows) and syncytiotrophoblasts (blue arrows). In the graph (D), data are represented as mean ± SD; **P < 0.001.

Fig. 6.

Schematic diagram illustrating the changes observed in preeclampsia to suggest a potential link between changes in cholesterol efflux and the alteration in cholesterol metabolism. The raised placental AIBP may contribute to the impaired angiogenesis/extravillous trophophlast (EVT) invasion, possibly leading to increased oxidative stress and endothelial dysfunction. In contrast, the increased placental CYP27A1, which parallels the increased 27-OHC placenta concentration may lead to the increased cholesterol efflux observed, thus dampening the lipid peroxidation and associated oxidative stress/endothelial dysfunction, providing a compensatory response.