| First Author | Soloviev DA | Year | 2014 |
| Journal | J Immunol | Volume | 193 |
| Issue | 9 | Pages | 4712-21 |
| PubMed ID | 25261488 | Mgi Jnum | J:318693 |
| Mgi Id | MGI:6843761 | Doi | 10.4049/jimmunol.1400202 |
| Citation | Soloviev DA, et al. (2014) Dual role of the leukocyte integrin alphaMbeta2 in angiogenesis. J Immunol 193(9):4712-21 |
| abstractText | Polymorphonuclear neutrophils (PMNs) and macrophages are crucial contributors to neovascularization, serving as a source of chemokines, growth factors, and proteases. alpha(M)beta(2)(CD11b/CD18) and alpha(L)beta(2)(CD11a/CD18) are expressed prominently and have been implicated in various responses of these cell types. Thus, we investigated the role of these beta2 integrins in angiogenesis. Angiogenesis was analyzed in wild-type (WT), alpha(M)-knockout (alpha(M)(-/-)), and alpha(L)-deficient (alpha(L)(-/-)) mice using B16F10 melanoma, RM1 prostate cancer, and Matrigel implants. In all models, vascular area was decreased by 50-70% in alpha(M)(-/-) mice, resulting in stunted tumor growth as compared with WT mice. In contrast, alpha(L) deficiency did not impair angiogenesis and tumor growth. The neovessels in alpha(M)(-/-) mice were leaky and immature because they lacked smooth muscle cell and pericytes. Defective angiogenesis in the alpha(M)(-/-) mice was associated with attenuated PMN and macrophage recruitment into tumors. In contrast to WT or the alpha(L)(-/-) leukocytes, the alpha(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 alpha(M)I-domain, the major ligand binding site in the beta(2) integrins, with Plg. However, the alpha(L)I-domain failed to bind Plg. In addition, endothelial cells failed to form tubes in the presence of conditioned medium collected from TNF-alpha-stimulated PMNs derived from the alpha(M)(-/-) mice because of severely impaired degranulation and secretion of VEGF. Thus, alpha(M)beta(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. |
