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Dual role of the leukocyte integrin ?M?2 in angiogenesis #MMPMID25261488
Soloviev DA; Hazen SL; Szpak D; Bledzka KM; Ballantyne CM; Plow EF; Pluskota E
J Immunol 2014[Nov]; 193 (9): 4712-21 PMID25261488show ga
Neutrophils (PMN) and macrophages are crucial contributors to neovascularization serving as a source of chemokines, growth factors and proteases. ?M?2(CD11b/CD18) and ?L?2(CD11a/CD18) are expressed prominently and have been implicated in various responses of these cell types. Thus, we investigated the role of these ?2 integrins in angiogenesis. Angiogenesis was analyzed in wild-type (WT), ?M-knockout (?M?/?) and ?L-deficient (?L?/?) mice using B16F10 melanoma, RM1 prostate cancer and matrigel implants. In all models, vascular area was decreased by 50?70% in ?M?/? mice resulting in stunted tumor growth as compared to WT mice. In contrast, ?L deficiency did not impair angiogenesis and tumor growth. The neovessels in ?M?/? mice were leaky and immature as they lacked smooth muscle cell and pericytes. Defective angiogenesis in the ?M?/? mice was associated with attenuated neutrophil (PMN) and macrophage recruitment into tumors. In contrast to WT or the ?L?/? leukocytes, the ?M?/? myeloid cells showed impaired plasmin (Plm)-dependent ECM invasion, resulting from 50?75% decrease in plasminogen (Plg) binding and pericellular Plm activity. Surface plasmon resonance verified direct interaction of the ?MI-domain, the major ligand binding site in the ?2 integrins, with Plg. However, the ?LI-domain failed to bind Plg. Also, endothelial cells failed to form tubes in the presence of conditioned medium collected from TNF-?-stimulated PMNs derived from the ?M?/? mice due to severely impaired degranulation and secretion of VEGF. Thus, ?M?2 plays a dual role in angiogenesis, supporting not only Plm-dependent recruitment of myeloid cells to angiogenic niches, but also secretion of VEGF by these cells.