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. αMβ2(CD11b/CD18) and αLβ2(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), αM-knockout (αM−/−), and αL-deficient (αL−/−) mice using B16F10 melanoma, RM1 prostate cancer, and Matrigel implants. In all models, vascular area was decreased by 50–70% in αM−/− mice, resulting in stunted tumor growth as compared with WT mice. In contrast, αL deficiency did not impair angiogenesis and tumor growth. The neovessels in αM−/− mice were leaky and immature because they lacked smooth muscle cell and pericytes. Defective angiogenesis in the αM−/− mice was associated with attenuated PMN and macrophage recruitment into tumors. In contrast to WT or the αL−/− leukocytes, the αM−/− 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 αMI-domain, the major ligand binding site in the β2 integrins, with Plg. However, the αLI-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 αM−/− mice because of severely impaired degranulation and secretion of VEGF. Thus, αMβ2 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.