title: On-site education of VEGF-recruited monocytes improves their performance as angiogenic and arteriogenic accessory cells.
abstract: Adult neovascularization relies on the recruitment of monocytes to the target organ or tumor and functioning therein as a paracrine accessory. The exact origins of the recruited monocytes and the mechanisms underlying their plasticity remain unclear. Using a VEGF-based transgenic system in which genetically tagged monocytes are conditionally summoned to the liver as part of a VEGF-initiated angiogenic program, we show that these recruited cells are derived from the abundant pool of circulating Ly6C(hi) monocytes. Remarkably, however, upon arrival at the VEGF-induced organ, but not the naive organ, monocytes undergo multiple phenotypic and functional changes, endowing them with enhanced proangiogenic capabilities and, importantly, with a markedly increased capacity to remodel existing small vessels into larger conduits. Notably, monocytes do not differentiate into long-lived macrophages, but rather appear as transient accessory cells. Results from transfers of presorted subpopulations and a novel tandem transfer strategy ruled out selective recruitment of a dedicated preexisting subpopulation or onsite selection, thereby reinforcing active reprogramming as the underlying mechanism for improved performance. Collectively, this study uncovered a novel function of VEGF, namely, on-site education of recruited "standard" monocytes to become angiogenic and arteriogenic professional cells, a finding that may also lend itself for a better design of angiogenic therapies.
authors.affiliation: Department of Developmental Biology and Cancer Research, the Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Avraham-Davidi
authors.forename: Simon
authors.initials: S
authors.lastname: Yona
authors.forename: Myriam
authors.initials: M
authors.lastname: Grunewald
authors.forename: Limor
authors.initials: L
authors.lastname: Landsman
authors.forename: Clement
authors.initials: C
authors.lastname: Cochain
authors.forename: Jean Sebastien
authors.initials: JS
authors.lastname: Silvestre
authors.forename: Haim
authors.initials: H
authors.lastname: Mizrahi
authors.forename: Mohammad
authors.initials: M
authors.lastname: Faroja
authors.forename: Dalit
authors.initials: D
authors.lastname: Strauss-Ayali
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001013:Aorta, Thoracic / Q000166:cytology / Q000254:growth & development; D017209:Apoptosis; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D008822:Mice, Transgenic; D009000:Monocytes / Q000145:classification / Q000166:cytology / Q000502:physiology*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*
chemical_list: D000950:Antigens, Ly; C494192:Ly-6C antigen, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse