Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia

Objective: Accumulating evidence suggests that the balance between vascular endothelial growth factor ( VEGF), placental growth factor ( PlGF), and their receptors is important for effective vasculogenesis, angiogenesis, and placental development. Recently, the soluble form of VEGFR-1 (sVEGFR-1), an antagonist to VEGF and PlGF, has been implicated in the pathophysiology of pre-eclampsia. Plasma sVEGFR-1 concentration is elevated in pre-eclampsia at the time of clinical diagnosis and correlates with the severity of the disease. The purpose of this study was to determine whether the concentrations of sVEGFR-1 in plasma of pre-eclamptic patients change prior to the clinical manifestations of the disease. Methods: A longitudinal case-control study was conducted in normal pregnant women ( n=44) and patients with preeclampsia ( n = 44). Blood sampling was performed at six intervals: ( 1) 7 - 16 weeks; ( 2) 16 - 24 weeks; ( 3) 24 - 28 weeks; ( 4) 28 - 32 weeks; ( 5) 32 - 36 weeks; and ( 6) more than 37 weeks of gestation. To examine the relationship between plasma sVEGFR-1 concentration and interval to clinical diagnosis of pre-eclampsia, plasma samples of pre-eclamptic patients at different gestational ages were stratified according to the interval from blood sampling to clinical development of the disease into five groups: ( 1) at clinical manifestation; ( 2) 2 - 5 weeks; ( 3) 6 - 10 weeks; ( 4) 11 - 16 weeks; and ( 5) 17 - 25 weeks before clinical manifestations. Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay. Parametric statistics and repeated measure procedures were used for the analysis. Results: The mean plasma sVEGFR-1 concentration in pre-eclamptic patients before the clinical manifestation of the disease was significantly higher than in normal pregnant women at 24 - 28, 28 - 32, and 32 - 37 weeks of gestation ( p = 0.02, p<0.001, and p<0.001, respectively). In contrast, no significant differences in the mean plasma sVEGFR-1 concentration between patients with pre-eclampsia and normal pregnant women were observed both at 7 - 16 weeks and 16 - 24 weeks of gestation ( p= 0.1 and p = 0.9). Similarly, the mean plasma sVEGFR-1 concentration was significantly higher in pre-eclamptic patients than in normal pregnant women at clinical manifestation, at 2 - 5 weeks ( mean 3.8 weeks), and at 6 - 10 weeks ( mean 8.2 weeks) prior to the development of clinical pre-eclampsia ( p<0.001, p<0.001, and p = 0.002, respectively). Among patients with early-onset pre-eclampsia ( defined as gestational age of 34 weeks or less), the mean plasma sVEGFR-1 concentration was significantly higher in pre-eclampsia ( before clinical diagnosis) than in normal pregnant women at 24 - 28 ( mean 26.4) weeks of gestation ( p = 0.008). In contrast, among patients with the late-onset disease ( defined as gestational age of more than 34 weeks), plasma sVEGFR-1 concentration in pre-clinical pre-eclampsia was significantly higher than in normal pregnant women at 28 - 32 ( mean 30.2) weeks of gestation ( p<0.001). Conclusions: Plasma sVEGFR-1 concentration is elevated in pre-eclampsia prior to the clinical diagnosis of the disease. This elevation began 6 - 10 weeks prior to the clinical manifestations, and the increase was more pronounced at 2 - 5 weeks before the diagnosis, as well as at clinical presentation. Furthermore, in early-onset pre-eclampsia, plasma concentration of sVEGFR-1 is elevated earlier than the late-onset disease.