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EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF.
- Source :
-
EMBO reports [EMBO Rep] 2018 May; Vol. 19 (5). Date of Electronic Publication: 2018 Apr 11. - Publication Year :
- 2018
-
Abstract
- 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.<br /> (© 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Subjects :
- Animals
Cells, Cultured
Endothelial Cells metabolism
Female
Humans
Intussusception
Ischemia pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, SCID
Muscle, Skeletal pathology
Neovascularization, Pathologic pathology
Phosphorylation
Vascular Endothelial Growth Factor Receptor-2 metabolism
Ephrin-B2 metabolism
Myoblasts metabolism
Neovascularization, Pathologic metabolism
Receptor, EphB4 metabolism
Signal Transduction
Vascular Endothelial Growth Factor A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1469-3178
- Volume :
- 19
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- EMBO reports
- Publication Type :
- Academic Journal
- Accession number :
- 29643120
- Full Text :
- https://doi.org/10.15252/embr.201745054