Circulating angiogenic factors in preeclampsia

VEGF has been proposed to play a part in the pre-eclamptic process. Initial studies showed serum levels of VEGF to be elevated in pre-eclampsia and suggested a role in endothelial cell activation (Baker et al., 1995). More recently, VEGF and VEGFR expression have been shown to be down-regulated in severe pre-eclampsia (Lyall etal., 1997; Zhou et al., 2002). This suggests impaired vascular development in the placenta and supports the hypothesis that the VEGF system has an important regulatory role in the process of trophoblastic invasion. Reduced endothelium-dependent relaxation of blood vessels incubated in pre-eclamptic serum in the presence of anti-VEGF antibody suggests a role for low concentrations of VEGF in the pathogenesis of pre-eclampsia (Brockelsby et al., 1999).

Soluble Flt-1 (sFlt-1), which binds VEGF, increases in the serum of women with pre-eclampsia (Koga et al., 2003; Maynard et al., 2003; Tsatsaris et al., 2003) as concentrations of circulating free PIGF and VEGF decrease, even prior to the onset of the clinical syndrome (Polliotti et al., 2003; Taylor et al., 2003). A pre-eclamptic-like state with hypertension, proteinuria and glomerular endothe-liosis was induced in pregnant rats by administering exogenous sFlt-1 (Maynard et al., 2003). Moreover, cancer patients treated with VEGF-signaling inhibitors have developed hypertension and proteinuria (Kabbinavar et al., 2003; Yang et al., 2003). Thus, excess sFlt-1 may indeed play an important role in the pathogenesis of pre-eclampsia.

In a cross-sectional study, sFlt-1 levels were shown to increase about 5 weeks prior to the onset of pre-eclampsia (Levine et al., 2004). In women destined to develop early-onset pre-eclampsia and intra-uterine growth restriction, there was a greater variation in sFlt-1 and PIGF levels, supporting a role for abnormal placental angiogenesis in the aetiology of pre-eclampsia.

During pregnancy, another antiangiogenic protein, soluble endoglin (a co-receptor for transforming growth factor ß! and ß3) is released into the maternal circulation from the placenta. Circulating soluble endoglin levels increase 2-3 months before the onset of pre-eclampsia (Levine etal., 2006). This rise in soluble endoglin concentration was usually accompanied by an increased ratio of sFlt-1: PIGF ratio. Combined together rising levels of these two values strongly predicts the future onset of pre-eclampsia (Levine etal., 2006).

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