Hypoxia is responsible for soluble vascular endothelial growth factor receptor-1 (VEGFR-1) but not for soluble endoglin induction in villous trophoblast

Carine Munaut, Sophie Lorquet, Christel Pequeux, Sylvia Blacher, Sarah Berndt, Francis Frankenne, Jean-Michel Foidart
Human Reproduction 2008, 23 (6): 1407-15

BACKGROUND: Pre-eclampsia is a pregnancy disorder characterized by a maternal endothelial cell dysfunction associated with low levels of circulating placental growth factor (PlGF) and increased levels of total vascular endothelial growth factor (VEGF), soluble VEGF receptor-1 (sVEGFR-1), and soluble endoglin, a transforming growth factor beta1 and 3 coreceptor. Here, we tested the hypothesis that these altered levels of angiogenic cytokines and of the anti-angiogenic soluble forms of cytokine receptors could be the consequence of hypoxia.

METHODS: Normal human umbilical vein endothelial cells, immortalized first trimester extravillous trophoblast cells (HTR8/SVneo) and first trimester placental villi explants (8-14 weeks) were used for culture under normoxia (20% O(2)) or hypoxia (1% O(2)). Culture media were collected for the measurement of cytokines by enzyme-linked immunosorbent assay. Total RNA was extracted for RT-PCR analysis.

RESULTS: Under hypoxia, villous trophoblast expressed higher levels of VEGF, VEGFR-1, sVEGFR-1 and VEGFR-2 mRNAs (P < 0.001), and secreted more VEGF and sVEGFR-1 proteins (P < 0.05). In contrast, PlGF mRNA and protein were decreased in 1% O(2) (P < 0.001), whereas endoglin (Eng) was not modulated. Additionally, sVEGFR-1 directly abolished VEGF/PlGF-induced angiogenesis in the rat aortic ring assay.

CONCLUSIONS: Our results support the hypotheses that, in pre-eclampsia, (i) overproduction of VEGF family factors by pre-eclamptic placenta is a consequence of induced hypoxia; (ii) overproduction of sVEGFR-1 by hypoxic villous trophoblast accounts for maternal free VEGF depletion; (iii) low circulating level of free PlGF is not only related to sVEGFR-1 overproduction, but also to hypoxia-induced mRNA down-regulation; (iv) Eng is not modulated by hypoxia.

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