Amps And Angiogenesis

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[20].

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[21]. 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[20]. 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[22].

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[23]. 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[24]. 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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