Dual role of the leukocyte integrin ?M?2 in angiogenesis.

ABSTRACT: Polymorphonuclear neutrophils (PMNs) 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 with WT mice. In contrast, ?(L) deficiency did not impair angiogenesis and tumor growth. The neovessels in ?(M)(-/-) mice were leaky and immature because they lacked smooth muscle cell and pericytes. Defective angiogenesis in the ?(M)(-/-) mice was associated with attenuated PMN and macrophage recruitment into tumors. In contrast to WT or the ?(L)(-/-) leukocytes, the ?(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 ?(M)I-domain, the major ligand binding site in the ?(2) integrins, with Plg. However, the ?(L)I-domain failed to bind Plg. In addition, endothelial cells failed to form tubes in the presence of conditioned medium collected from TNF-?-stimulated PMNs derived from the ?(M)(-/-) mice because of 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.

SUBMITTER: Soloviev DA 

PROVIDER: S-EPMC4201972 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature