PI(4,5)P2-dependent regulation of endothelial tip cell specification contributes to angiogenesis

Journal article

Davies, Elizabeth M., Gurung, Rajendra, Le, Kai Qin, Roan, Katherine T. T., Harvey, Richard P., Mitchell, Geraldine M., Schwarz, Quenten and Mitchell, Christina A.. (2023). PI(4,5)P2-dependent regulation of endothelial tip cell specification contributes to angiogenesis. Science Advances. 9(13), p. Article eadd6911. https://doi.org/10.1126/sciadv.add6911
AuthorsDavies, Elizabeth M., Gurung, Rajendra, Le, Kai Qin, Roan, Katherine T. T., Harvey, Richard P., Mitchell, Geraldine M., Schwarz, Quenten and Mitchell, Christina A.
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.

Year2023
JournalScience Advances
Journal citation9 (13), p. Article eadd6911
PublisherAmerican Association for the Advancement of Science
ISSN2375-2548
Digital Object Identifier (DOI)https://doi.org/10.1126/sciadv.add6911
PubMed ID37000875
Scopus EID2-s2.0-85151378240
PubMed Central IDPMC10065449
Open accessPublished as ‘gold’ (paid) open access
Page range1-23
FunderNational Health and Medical Research Council (NHMRC)
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File Access Level
Open
Output statusPublished
Publication dates
Online31 Mar 2023
Publication process dates
Accepted24 Feb 2023
Deposited01 Apr 2025
Grant IDGNT1010368
Additional information

Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC) (https://creativecommons.org/licenses/by-nc/4.0/).

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