2023
Sci Adv. 2023 Mar 31;9(13):eadd6911. doi: 10.1126/sciadv.add6911. Epub 2023 Mar 31.
PI(4,5)P2-dependent regulation of endothelial tip cell specification contributes to angiogenesis
Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. School of Clinical Medicine and School of Biotechnology and Biomolecular Science, University of New South Wales, Kensington, New South Wales 2052, Australia. O'Brien Institute Department of St Vincent's Institute and University of Melbourne, Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria 3065, Australia. Health Sciences Faculty, Australian Catholic University, Fitzroy, Victoria 3065, Australia. Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia 5001, Australia.
Service type: Knockout mice
Abstract
Dynamic positioning of endothelial tip and stalk cells, via the interplay between VEGFR2 and NOTCH signaling, is essential for angiogenesis. VEGFR2 activates PI3K, which phosphorylates PI(4,5)P2 to PI(3,4,5)P3, activating AKT; however, PI3K/AKT does not direct tip cell specification. We report that PI(4,5)P2 hydrolysis by the phosphoinositide-5-phosphatase, INPP5K, contributes to angiogenesis. INPP5K ablation disrupted tip cell specification and impaired embryonic angiogenesis associated with enhanced DLL4/NOTCH signaling. INPP5K degraded a pool of PI(4,5)P2 generated by PIP5K1C phosphorylation of PI(4)P in endothelial cells. INPP5K ablation increased PI(4,5)P2, thereby releasing β-catenin from the plasma membrane, and concurrently increased PI(3,4,5)P3-dependent AKT activation, conditions that licensed DLL4/NOTCH transcription. Suppression of PI(4,5)P2 in INPP5K-siRNA cells by PIP5K1C-siRNA, restored β-catenin membrane localization and normalized AKT signaling. Pharmacological NOTCH or AKT inhibition in vivo or genetic β-catenin attenuation rescued angiogenesis defects in INPP5K-null mice. Therefore, PI(4,5)P2 is critical for β-catenin/DLL4/NOTCH signaling, which governs tip cell specification during angiogenesis.
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