Novel Splice Variants of sFlt1 are Upregulated in Preeclampsia

Abstract 

Soluble fms-like tyrosine kinase-1 (sFlt1) is a truncated splice variant of Flt1, which is upregulated in preeclampsia. In this study we sought to characterize the unique C-terminus of sFlt. Through bioinformatic analyses, we identified two novel sFlt1 splice variants and two previously described sFlt1 splice variants. The novel variants are identical to the previously described sFlt1_v1 through exon 13, but then diverge to unique 3′ termini consisting of a novel exon 15 (sFlt1_v2 and sFlt1_v3) or an extension of exon 14 (sFlt1_v4). Quantitative PCR showed that three out of four sFlt variants were upregulated in placenta of women with preeclampsia. Mass spectrometry analysis of sFlt1 purified from placental serum confirmed the presence of sFlt1_v1 protein, and an additional variant which includes sequence derived from exon 14. siRNA experiments targeting each variant confirmed that three of the four variants contribute significantly to total sFlt1 expression by cytotrophoblasts in vitro. These findings provide evidence that human placenta expresses a family of sFlt1 splice variants, at least three of which are expressed as proteins, and which appear to be globally upregulated in preeclampsia.

Keywords: Preeclampsia, Hypertension, Pregnancy, Placenta