title: Dual role of the leukocyte integrin αMβ2 in angiogenesis.
abstract: Polymorphonuclear neutrophils (PMNs) and macrophages are crucial contributors to neovascularization, serving as a source of chemokines, growth factors, and proteases. α(M)β(2)(CD11b/CD18) and α(L)β(2)(CD11a/CD18) are expressed prominently and have been implicated in various responses of these cell types. Thus, we investigated the role of these β2 integrins in angiogenesis. Angiogenesis was analyzed in wild-type (WT), α(M)-knockout (α(M)(-/-)), and α(L)-deficient (α(L)(-/-)) mice using B16F10 melanoma, RM1 prostate cancer, and Matrigel implants. In all models, vascular area was decreased by 50-70% in α(M)(-/-) mice, resulting in stunted tumor growth as compared with WT mice. In contrast, α(L) deficiency did not impair angiogenesis and tumor growth. The neovessels in α(M)(-/-) mice were leaky and immature because they lacked smooth muscle cell and pericytes. Defective angiogenesis in the α(M)(-/-) mice was associated with attenuated PMN and macrophage recruitment into tumors. In contrast to WT or the α(L)(-/-) leukocytes, the α(M)(-/-) myeloid cells showed impaired plasmin (Plm)-dependent extracellular matrix invasion, resulting from 50-75% decrease in plasminogen (Plg) binding and pericellular Plm activity. Surface plasmon resonance verified direct interaction of the α(M)I-domain, the major ligand binding site in the β(2) integrins, with Plg. However, the α(L)I-domain failed to bind Plg. In addition, endothelial cells failed to form tubes in the presence of conditioned medium collected from TNF-α-stimulated PMNs derived from the α(M)(-/-) mice because of severely impaired degranulation and secretion of VEGF. Thus, α(M)β(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.
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Learner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Soloviev
authors.affiliation: Department of Molecular and Cellular Medicine, Cleveland Clinic, Cleveland, OH 44195; and.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Learner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Dorota
authors.initials: D
authors.lastname: Szpak
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Learner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Kamila M
authors.initials: KM
authors.lastname: Bledzka
authors.affiliation: Baylor College of Medicine and Methodist DeBakey Heart and Vascular Center, Houston, TX 77030.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Learner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Learner Research Institute, Cleveland Clinic, Cleveland, OH 44195; pluskote@ccf.org.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pluskota
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016177:Macrophage-1 Antigen; D042461:Vascular Endothelial Growth Factor A; D010958:Plasminogen