title: VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue.
abstract: Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b(+)/Gr-1(+)/CXCR4(hi) neutrophils, were observed at the site of engraftment, whereas VEGF-A-deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1α. VEGF-A-recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9-deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b(+)/Gr-1(+) neutrophils that are CXCR4(hi) and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Gustaf
authors.initials: G
authors.lastname: Christoffersson
authors.forename: Evelina
authors.initials: E
authors.lastname: Vågesjö
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vandooren
authors.forename: Majken
authors.initials: M
authors.lastname: Lidén
authors.forename: Sara
authors.initials: S
authors.lastname: Massena
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Reinert
authors.forename: Marcela
authors.initials: M
authors.lastname: Brissova
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.forename: Mia
authors.initials: M
authors.lastname: Phillipson
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D000860:Hypoxia; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000098:blood supply / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism*; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C503133:Gr-1 protein, mouse; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9