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EphrinB2/EphB4 signaling regulates non‐sprouting angiogenesis by VEGF
Author(s) -
Groppa Elena,
Brkic Sime,
Uccelli Andrea,
Wirth Galina,
KorpisaloPirinen Petra,
Filippova Maria,
Dasen Boris,
Sacchi Veronica,
Muraro Manuele Giuseppe,
Trani Marianna,
Reginato Silvia,
GianniBarrera Roberto,
YläHerttuala Seppo,
Banfi Andrea
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201745054
Subject(s) - angiogenesis , sprouting , microbiology and biotechnology , signal transduction , sprouting angiogenesis , neovascularization , vegf receptors , chemistry , biology , cancer research , botany
Vascular endothelial growth factor ( VEGF ) is the master regulator of angiogenesis, whose best‐understood mechanism is sprouting. However, therapeutic VEGF delivery to ischemic muscle induces angiogenesis by the alternative process of intussusception, or vascular splitting, whose molecular regulation is essentially unknown. Here, we identify ephrinB2/EphB4 signaling as a key regulator of intussusceptive angiogenesis and its outcome under therapeutically relevant conditions. EphB4 signaling fine‐tunes the degree of endothelial proliferation induced by specific VEGF doses during the initial stage of circumferential enlargement of vessels, thereby limiting their size and subsequently enabling successful splitting into normal capillary networks. Mechanistically, EphB4 neither inhibits VEGF ‐R2 activation by VEGF nor its internalization, but it modulates VEGF ‐R2 downstream signaling through phospho‐ ERK 1/2. In vivo inhibitor experiments show that ERK 1/2 activity is required for EphB4 regulation of VEGF ‐induced intussusceptive angiogenesis. Lastly, after clinically relevant VEGF gene delivery with adenoviral vectors, pharmacological stimulation of EphB4 normalizes dysfunctional vascular growth in both normoxic and ischemic muscle. These results identify EphB4 as a druggable target to modulate the outcome of VEGF gene delivery and support further investigation of its therapeutic potential.