The role of the FLT1 gene alternative splicing in the fetal growth retardation development

Background. Fetal growth r estriction (FGR) is a major pregnancy complication often associated with placental dysfunction and angiogenic imbalance. The FLT1 gene encodes VEGFR-1, producing both membrane receptors and soluble isoforms (sFlt-1) through alternative splicing. Soluble variants sequester VEGF/PlGF and suppress angiogenesis. While the role of sFlt-1 in preeclampsia is widely studied, its splicing regulation and contribution to FGR remain unclear. The aim. T o evaluat e the alternative splicing role of the FLT1 gene expressed in placental decidual cells in the molecular mechanisms of fetal growth retardation. Materials and methods. The study included biopsies of the placenta maternal part of patients with physiological pregnancy (n = 8) and FGR (n = 13). RNA sequencing was performed on the Illumina NextSeq 2000 platform. Alternative splicing events were identified and quantified using the MAJIQ program. Results. T his work provides the first analysis of FLT1 gene alternative splicing in decidual cells during FGR. Four splicing events were shared across both groups, including exon skipping, intron retention, and a complex event with two sub-events. The FGR group additionally demonstrated a unique complex event and three intron retentions absent in controls. These changes indicate a shift toward enhanced production of soluble VEGFR-1 isoforms, which act as antiangiogenic “traps”, reduce uteroplacental blood flow, and contribute to growth restriction. Conclusions. Alternativ e splicing of the FLT1 gene plays an important role in the FGR pathogenesis. Excessive intron retention and exon skipping lead to increased expression of shortened antiangiogenic proteins, disrupting the balance of angiogenesis and contributing to placental dysfunction.