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| Item Type: | Article |
|---|---|
| Title: | LINC00607 facilitates endothelial VEGF-A receptor FLT1 splicing |
| Creators: |
Lam, Frederike, Warwick, Timothy, Oo, James A., Krüger, Agnes Y., Kreis, Nina-Naomi, Diagel, Anastasiia, Ponce, Judit Izquierdo, Tirunagari, Praveenya, Bayer, Marie E., Nonn, Olivia  ORCID: https://orcid.org/0000-0001-6385-2866, Dechend, Ralf ORCID: https://orcid.org/0000-0001-6636-3080, Walther, Thomas, Boon, Reinier A., Baker, Andrew H., Günther, Stefan, Wittig, Ilka, Chen, Zhifen, Müller-McNicoll, Michaela, Louwen, Frank, Brandes, Ralf P. and Leisegang, Matthias S. ORCID: https://orcid.org/0000-0003-3692-7142
|
| Abstract: | 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. |
| Keywords: | Alternative Splicing, Angiogenesis, Exons, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells, Long Noncoding RNA, Pre-Eclampsia, Pregnancy, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1, Animals |
| Source: | Molecular Therapy |
| ISSN: | 1525-0016 |
| Publisher: | Elsevier / Cell Press |
| Volume: | 34 |
| Number: | 7 |
| Page Range: | 4323-4338 |
| Date: | 1 July 2026 |
| Official Publication: | https://doi.org/10.1016/j.ymthe.2026.03.038 |
| PubMed: | View item in PubMed |
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