Complement activation and its potential effect on macrophage-mediated inhibition of angiogenesis. The proteolytic activation of C3 can be mediated by the classical, lectin, and alternative pathways, initiated by C1 complex, mannose-binding lectin, and H2O-bound C3, respectively. C3 produces C3a and C3b, which can participate in both the alternative pathway C3 convertase (amplification) and C5 convertase. C5 produces C5a and C5b, which can recruit C6, C7, C8, and C9 to form the terminal membrane attack complex causing pore formation and cell destruction. C3a and C5a anaphylotoxins bind to receptors (C3aR and C5aR) on monocytes/macrophages and many other cells causing an antiangiogenic response reflected by increased IL-6, TNF-α, sVEGFR1, and decreased IL-10 mRNA. Increased sVEGFR1 secretion from monocytes/macrophages inhibits hypoxia-driven retinal neovascularization and Matrigel angiogenesis. (Professional illustration by A. Y. Chen.)
