Gatekeeping role of Nf2/Merlin in vascular tip EC induction through suppression of VEGFR2 internalization

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In sprouting angiogenesis, the precise mechanisms underlying how intracellular vascular endothelial growth factor receptor 2 (VEGFR2) signaling is higher in one endothelial cell (EC) compared with its neighbor and acquires the tip EC phenotype under a similar external cue are elusive. Here, we show that Merlin, encoded by the neurofibromatosis type 2 (NF2) gene, suppresses VEGFR2 internalization depending on VE-cadherin density and inhibits tip EC induction. Accordingly, endothelial Nf2 depletion promotes tip EC induction with excessive filopodia by enhancing VEGFR2 internalization in both the growing and matured vessels. Mechanistically, Merlin binds to the VEGFR2-VE-cadherin complex at cell-cell junctions and reduces VEGFR2 internalization-induced downstream signaling during tip EC induction. As a consequence, nonfunctional excessive sprouting occurs during tumor angiogenesis in EC-specific Nf2-deleted mice, leading to delayed tumor growth. Together, Nf2/Merlin is a crucial molecular gatekeeper for tip EC induction, capillary integrity, and proper tumor angiogenesis by suppressing VEGFR2 internalization.
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Issue Date
2022-06
Language
English
Article Type
Article
Citation

SCIENCE ADVANCES, v.8, no.23

ISSN
2375-2548
DOI
10.1126/sciadv.abn2611
URI
http://hdl.handle.net/10203/297275
Appears in Collection
BS-Journal Papers(저널논문)MSE-Journal Papers(저널논문)
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