VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue.

Christoffersson G, Vågesjö E, Vandooren J, Lidén M, Massena S, Reinert RB, Brissova M, Powers AC, Opdenakker G, Phillipson M
Blood. 2012 120 (23): 4653-62

PMID: 22966168 · PMCID: PMC3512240 · DOI:10.1182/blood-2012-04-421040

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.

MeSH Terms (21)

Animals CD11b Antigen Chemokine CXCL12 Female Hypoxia Immunohistochemistry Islets of Langerhans Islets of Langerhans Transplantation Male Matrix Metalloproteinase 9 Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Confocal Microscopy, Video Neovascularization, Physiologic Neutrophil Infiltration Neutrophils Receptors, Chemokine Receptors, CXCR4 Vascular Endothelial Growth Factor A

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