科研之友
微信
新浪微博
Facebook
分享链接
摘要
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 beta(2) 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 WTor 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 aMI-domain, the major ligand binding site in the beta(2) integrins, with Plg. However, the alpha I-L-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.
- 出版日期2014-11-1
