Targeting Angiogenesis: A therapeutic approach using a synthetic derived peptide

Abstract

Angiogenesis plays a critical role in processes such as organ development, wound healing, and tumor growth. It requires well‐orchestrated integration of soluble and matrix factors and timely recognition of such signals to regulate this process. Previous work has shown that endothelial cells express CXC receptor 3 (CXCR3) late in wound regeneration, and upon ligandation by IP‐10 (CXCL10) new vessels are prevented and immature vessels involute. To develop new therapeutic agents to inhibit or collapse blood vessel formation and/or involution of newly forming vessels we isolated a 21 amino acid fragment, residues 78–98, which we modeled to be the functional domain of IP‐10 (IP10p) and analyzed its ability to modulate endothelial cell tube formation. Treatment of the endothelial cells with the IP‐10 peptide significantly inhibited VEGF‐induced endothelial motility and tube formation, a response critical for angiogenesis. [Using an in vivo Matrigel assay we show that the IP‐10p is able to inhibit vessel formation and induce vessel dissociation] Furthermore, stimulation of CXCR3 by the IP‐10 or the IP‐10 peptide induced an increase in cAMP production and activation of PKA that leads to the inhibition of VEGF‐mediated m‐calpain activation and thereby limits cell motility. We propose that this peptide provides a novel reagent that inhibits endothelial signaling pathway thus, allowing for the modulation angiogenesis.