title: Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils.
abstract: The granulocyte colony-stimulating factor (G-CSF) promotes angiogenesis. However, the exact mechanism is not known. We demonstrate that vascular endothelial growth factor (VEGF) was released by Gr-1+CD11b- neutrophils but not Gr-1-CD11b+ monocytes prestimulated with G-CSF in vitro and in vivo. Similarly, in vivo, concomitant with an increase in neutrophil numbers in circulation, G-CSF augmented plasma VEGF level in vivo. Local G-CSF administration into ischemic tissue increased capillary density and provided a functional vasculature and contributed to neovascularization of ischemic tissue. Blockade of the VEGF pathway abrogated G-CSF-induced angiogenesis. On the other hand, as we had shown previously, VEGF can induce endothelial progenitor cell (EPC) mobilization. Here, we show that G-CSF also augmented the number of circulating VEGF receptor-2 (VEGFR2) EPCs as compared with untreated controls. Blocking the VEGF/VEGFR1, but to a much lesser extent, the VEGF/VEGFR2 pathway in G-CSF-treated animals delayed tissue revascularization in a hindlimb model. These data clearly show that G-CSF modulates angiogenesis by increasing myelomonocytic cells (VEGFR1+ neutrophils) and their release of VEGF. Our results indicated that administration of G-CSF into ischemic tissue provides a novel and safe therapeutic strategy to improve neovascularization.
authors.affiliation: Department of Cardiology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ohki
authors.forename: Beate
authors.initials: B
authors.lastname: Heissig
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Sato
authors.forename: Haruyo
authors.initials: H
authors.lastname: Akiyama
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Kazunori
authors.initials: K
authors.lastname: Shimada
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
authors.forename: Koichi
authors.initials: K
authors.lastname: Hattori
authors.forename: Akimichi
authors.initials: A
authors.lastname: Ohsaka
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D002196:Capillaries / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007511:Ischemia / Q000473:pathology; D007797:Laminin / Q000737:chemistry; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015233:Models, Statistical; D009000:Monocytes / Q000166:cytology; D009389:Neovascularization, Pathologic; D009504:Neutrophils / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D016179:Granulocyte Colony-Stimulating Factor; D003094:Collagen; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2