EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF

Groppa, Elena and Brkic, Sime and Uccelli, Andrea and Wirth, Galina and Korpisalo-Pirinen, Petra and Filippova, Maria and Dasen, Boris and Sacchi, Veronica and Muraro, Manuele Giuseppe and Trani, Marianna and Reginato, Silvia and Gianni-Barrera, Roberto and Ylä-Herttuala, Seppo and Banfi, Andrea. (2018) EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF. EMBO reports, 19 (5). e45054.

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Official URL: https://edoc.unibas.ch/65689/

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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-ERK1/2.; In vivo; inhibitor experiments show that ERK1/2 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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Cell and Gene Therapy (Banfi)
UniBasel Contributors:Banfi, Andrea
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:17 Oct 2018 08:07
Deposited On:17 Oct 2018 08:07

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