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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\u00a0days by Aflibercept treatment. Vascular stabilization was fastest with low VEGF, but delayed or prevented by higher doses, without affecting pericyte coverage. Rather, VEGF dose\u2010dependently inhibited endothelial Semaphorin3A expression, thereby impairing recruitment of Neuropilin\u20101\u2010expressing monocytes (NEM), TGF\u2010\u03b21 production and endothelial SMAD2\/3 activation. TGF\u2010\u03b21 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\u2010\u03b21 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\u2010\u03b21 paracrine axis and Semaphorin3A treatment accelerates stabilization of VEGF\u2010induced angiogenesis.<\/jats:p>","DOI":"10.15252\/emmm.201405003","type":"journal-article","created":{"date-parts":[[2015,8,31]],"date-time":"2015-08-31T21:10:03Z","timestamp":1441055403000},"page":"1366-1384","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin\u20101+ monocyte\/TGF\u2010\u03b21 paracrine axis"],"prefix":"10.1038","volume":"7","author":[{"given":"Elena","family":"Groppa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sime","family":"Brkic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuela","family":"Bovo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Reginato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Sacchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nunzia","family":"Di Maggio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuele G","family":"Muraro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Calabrese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Heberer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Gianni\u2010Barrera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Banfi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,9,7]]},"reference":[{"key":"BFEMMM201405003_CR1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/nrm2639","volume":"10","author":"HG Augustin","year":"2009","unstructured":"Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin\u2010Tie system. 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