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dc.contributor.authorGroppa, E
dc.contributor.authorBrkic, S
dc.contributor.authorUccelli, A
dc.contributor.authorWirth, G
dc.contributor.authorKorpisalo-Pirinen, P
dc.contributor.authorFilippova, M
dc.contributor.authorDasen. B
dc.contributor.authorSacchi, V
dc.contributor.authorMuraro, MG
dc.contributor.authorTrani, M
dc.contributor.authorReginato, S
dc.contributor.authorGianni-Barrera, R
dc.contributor.authorYlä-Herttuala, S
dc.contributor.authorBanfi A
dc.date.accessioned2018-04-17T07:56:59Z
dc.date.available2018-04-17T07:56:59Z
dc.date.issued2018
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/6524
dc.description.abstractVascular 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.
dc.language.isoEN
dc.publisherEMBO
dc.relation.ispartofseriesEMBO REPORTS
dc.relation.urihttp://dx.doi.org/10.15252/embr.201745054
dc.rightsCC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectEphB4
dc.subjectEphrinB2
dc.subjectintussusception
dc.subjectvascular endothelial growth factor
dc.titleEphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF
dc.description.versionpublished version
dc.contributor.departmentA.I. Virtanen -instituutti
uef.solecris.id53847203en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© Authors
dc.relation.doi10.15252/embr.201745054
dc.description.reviewstatuspeerReviewed
dc.relation.articlenumbere45054
dc.relation.issn1469-221X
dc.relation.issue4
dc.relation.volume19
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessOpen access -julkaisukanavassa ilmestynyt julkaisu


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