Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) and soluble Flt-1 by oxygen - a review

Morphological studies show poor placental vascular development and an increase in the mitotic index of cytotrophoblast cells in intrauterine growth restriction (IUGR). We hypothesized that the reported relatively high oxygen level in the intervillous space in contact with IUGR placental villi will limit angiogenesis by changes in vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) expression and function. Western immunoblot analysis demonstrates a diametric expression of PIGF and VEGF proteins throughout pregnancy, with P1GF levels increasing and VEGF levels decreasing, consistent with placental oxygenation. PIGF mRNA and protein is increased in IUGR as compared to gestationally matched normal placentae. Increasing oxygen tension upregulates P1GF protein in term placental villous explants, whereas hypoxia downregulates P1GF and VEGFR-1 (Flt-1) autophosphorylation in term trophoblast choriocarcinoma cell line (BeWo). Levels of soluble Flt-1 (sFlt-1) protein in supernatant of term villous explants were upregulated by 1 per cent hypoxia, whereas hyperoxia (40 per cent) decreased sFlt-1 levels, indicating that under conditions of increasing oxygen tension, PlGF function may remain unopposed. The addition of PlGF-1 to a spontaneously transformed first trimester cytotrophoblast cell line (ED₂₇) stimulated cell proliferation while PlGF-2 had little effect. In contrast, the addition of PlGF-1 had little effect on endothelial cell proliferation while this was inhibited by PIGF-2. Taken together these changes provide a molecular explanation for the observed poor angiogenesis in the pathogenesis of IUGR.