LINC00607 facilitates endothelial VEGF-A receptor FLT1 splicing.

Angiogenesis is a key function of vascular endothelial cells and becomes aberrant in pathologies such as preeclampsia. An important mediator of angiogenesis is vascular endothelial growth factor (VEGF) receptor FLT1; however, alternative splicing of FLT1 can generate soluble FLT1 (sFLT1), a decoy receptor that inhibits VEGF signaling. While some long non-coding RNAs (lncRNAs) are known to regulate splicing, their roles in endothelial biology remain poorly defined. Here, we identify lncRNA LINC00607 as a critical regulator of FLT1 alternative splicing. Loss of LINC00607 increased the formation of the anti-angiogenic sFLT1. CRISPR-mediated knockout of LINC00607 promoted exon 15 inclusion in FLT1, elevating sFLT1 levels and blunting VEGF-driven angiogenesis-a defect reversed by sFLT1-neutralizing antibodies. LINC00607 interacted with U2 small nuclear RNA (snRNA) to regulate exon 15 inclusion in FLT1, an interaction dependent on the chromatin-remodeler BRG1. A splice-blocking morpholino targeting the FLT1 intron14/exon15 junction specifically inhibited sFLT1 production by interacting with LINC00607 and U2 snRNA, and its application increased VEGF-A-mediated sprouting. LINC00607 expression inversely correlated with sFLT1 levels in vascular diseases. In preeclampsia, a multisystem pregnancy disorder involving hypertension and proteinuria, LINC00607 was downregulated in early and late-stage preeclampsia compared with healthy pregnancies. LINC00607 therefore fine-tunes VEGF signaling and might contribute to the pathophysiology of preeclampsia.