JOURNAL ARTICLE

Hypoxia-induced increase in soluble Flt-1 production correlates with enhanced oxidative stress in trophoblast cells from the human placenta

H Li, B Gu, Y Zhang, D F Lewis, Y Wang
Placenta 2005, 26 (2-3): 210-7
15708122

OBJECTIVE: Placental trophoblast cells (TCs) produce soluble Flt-1 (sFlt-1). Hypoxia induces placental oxidative stress and modulates trophoblast function. The aim of this study was to investigate whether hypoxia mediates TC sFlt-1 production and whether increased sFlt-1 production correlates with increased oxidative stress in placental TCs.

METHODS: Placentas were obtained immediately after delivery from normal pregnant women (n = 8). Placental TCs were isolated by Dispase digestion of villous tissue and purified by Percoll gradient centrifugation. Isolated TCs were cultured under normoxia (21% O2: 5% CO2/95% air) and hypoxia (2% O2/5% CO2/93% N2) conditions for 3 days in vitro. TC productions of sFlt-1, VEGF, and PlGF were measured by enzyme-linked immunosorbent assay (ELISA). Lipid peroxide production and superoxide dismutase (CuZn-SOD) levels were evaluated. Messenger RNA expressions of Flt-1, VEGF and PlGF were determined by RT-PCR. Messenger RNA expressions for superoxide dismutase (CuZn-SOD) and heme oxygenase-1 (HO-1) were also determined. Data are expressed as mean +/- SE. A p level less than 0.05 was considered statistically different.

RESULTS: Our results show that sFlt-1 production was significantly increased by TCs cultured under hypoxia condition that correlates with increased lipid peroxide production. We also found that under hypoxia condition: (1) the ratio of PlGF/VEGF production was reversed; (2) the ratio of lipid peroxides to superoxide dismutase production was increased. The increased mRNA expressions for Flt-1 and VEGF and the decreased mRNA expression for PlGF in TCs were consistent with the protein productions under hypoxia condition.

CONCLUSION: We concluded that upregulation of sFlt-1 and unbalanced PlGF/VEGF production associated with increased oxidative stress are consequences of hypoxia in placental TCs. Our results suggest that placental TCs are major sources of sFlt-1 and VEGF levels in the maternal circulation in women with preeclampsia.

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