AMPs are host defense molecules and in addition are involved in processes that take place during an early immune reaction. Cathelicidins regulate inflammation and repair processes. The cathelicidin LL-37/hCAP-18 modulates angiogenesis by a direct effect on endothelial cells involving the specific receptor FPRL1.
The mechanism of angiogenic activity of LL-37 is dependent on binding of the peptide to FPRL1, a G protein-coupled receptor recently found to mediate cellular responses to LL-37. It could be demonstrated that endothelial cells express functional FPLR1. The effect of LL-37 on vessel growth is supported by in vitro and in vivo experiments. Application of LL-37 in vivo resulted in vessel growth in models of physiologic and pathologic angiogenesis. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascular-ization in vivo. Application of the peptide in an angiogenesis model using the dorsal skinfold chamber in mice also showed induction of vessel growth.
PR39 is a further cathelicidin peptides, however, structurally unrelated to LL-37 or CRAMP. PR39 inhibits the ubiquitin-proteasome-dependent degradation of hypoxia-inducible factor-1a protein, resulting in accelerated formation of vascular structures in vitro and increased myocardial vasculature in mice. Coronary flow studies demonstrated that PR39-induced angiogenesis resulted in the production of functional blood vessels.
Also defensins have been linked to angiogenesis in the context of tumor biology. p-defensins and Vegf-A cooperate to promote tumor vasculogenesis by carrying out distinct tasks: p-defensins chemoattract DC precursors through CCR6, whereas Vegf-A primarily induces their endothelial-like specialization and migration to vessels, which is mediated by Vegf receptor-2.
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