EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF
| Autor: | Petra Korpisalo‐Pirinen, Marianna Trani, Elena Groppa, Andrea Uccelli, Sime Brkic, Silvia Reginato, Manuele G. Muraro, Veronica Sacchi, Galina Wirth, Roberto Gianni-Barrera, Seppo Ylä-Herttuala, Andrea Banfi, Maria Filippova, Boris Dasen |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A Vascular Biology & Angiogenesis Angiogenesis Receptor EphB4 Ephrin-B2 Mice SCID Gene delivery Biochemistry Article Myoblasts 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Intussusception (blood vessel growth) Ischemia Genetics Medicine Animals Humans Phosphorylation Intussusceptive angiogenesis Muscle Skeletal Molecular Biology Cells Cultured Sprouting angiogenesis intussusception Mice Knockout vascular endothelial growth factor Neovascularization Pathologic business.industry EphB4 Endothelial Cells Kinase insert domain receptor Articles Vascular Endothelial Growth Factor Receptor-2 Vascular endothelial growth factor Mice Inbred C57BL Vascular endothelial growth factor A 030104 developmental biology chemistry 030220 oncology & carcinogenesis Cancer research Female business EphrinB2 Signal Transduction |
| Zdroj: | EMBO Reports |
| DOI: | 10.5451/unibas-ep65689 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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