| Autor: |
Groppa E., Brkic S., Bovo E., Reginato S., Sacchi V., Di Maggio N., Muraro M. G., Calabrese D., Heberer M., Gianni-Barrera R., Banfi A. |
| Rok vydání: |
2015 |
| Zdroj: |
EMBO Molecular Medicine |
| DOI: |
10.15252/emmm.201405003 |
| Popis: |
VEGF is widely investigated for therapeutic angiogenesis but while short term delivery is desirable for safety it is insufficient for new vessel persistence jeopardizing efficacy. Here we investigated whether and how VEGF dose regulates nascent vessel stabilization to identify novel therapeutic targets. Monoclonal populations of transduced myoblasts were used to homogeneously express specific VEGF doses in SCID mouse muscles. VEGF was abrogated after 10 and 17 days by Aflibercept treatment. Vascular stabilization was fastest with low VEGF but delayed or prevented by higher doses without affecting pericyte coverage. Rather VEGF dose dependently inhibited endothelial Semaphorin3A expression thereby impairing recruitment of Neuropilin 1 expressing monocytes (NEM) and decreasing TGF ß1 and endothelial SMAD2/3 activation. TGF ß1 further initiated a feedback loop stimulating endothelial Semaphorin3A expression thereby amplifying the stabilizing signals. Blocking experiments showed that NEM recruitment required endogenous Semaphorin3A and that TGF ß1 was necessary to start the Semaphorin3A/NEM axis. Conversely Semaphorin3A treatment promoted NEM recruitment and vessel stabilization despite high VEGF doses or transient adenoviral delivery. Therefore VEGF inhibits the endothelial Semaphorin3A/NEM/TGF ß1 paracrine axis and Semaphorin3A treatment accelerates stabilization of VEGF induced angiogenesis. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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