FLT1 regulates VEGF signaling in a cell-intrinsic manner

Vascular Endothelial Growth Factor-A (VEGF) is a major angiogenic factor promoting cell proliferation, survival, migration, and permeability. VEGF signaling is suppressed by the decoy receptor Vascular Endothelial Growth Factor Receptor 1 (VEGFR1, or FLT1). FLT1 is alternatively spliced to produce a transmembrane isoform (mFLT1) and a secreted soluble isoform (sFLT1) which act as decoys to sequester VEGF ligand. This is thought to happen at the cell surface and in the extracellular matrix (ECM), but the reason for the large presence of FLT1 receptors inside the cell is not understood. Here, we investigate a novel role for FLT1 in modifying intracellular VEGF signaling. We show that both sFLT1 and mFLT1 colocalize with VEGF/VEGFR2 complexes in endothelial cells, and overexpression of sFLT1 in vitro inhibits VEGF signaling in a cell intrinsic manner. This suggests a novel role for FLT1 in both canonical and autocrine VEGF signaling through cell intrinsic suppression of VEGFR2 expression and signaling, which may impact therapeutics targeting the VEGF signaling pathway.