Induction of Angiogenesis by Active Matrix Metalloproteinses-2 and 9: Role of VEGF

Abstract

Abstract: : Purpose: Matrix metalloproteinases (MMPs) are a specialized group of enzymes that participate in extracellular matrix (ECM) degradation and have been postulated to play an important role in angiogenesis. The purpose of this study was to determine if active MMPs could induce angiogenesis in vivo. Methods: The chick chorio-allantoic membrane (CAM) assay was used as an in vivo angiogenesis model in this study. Methylcellulose discs containing pro or active MMPs were placed on 6 day CAMs and analyzed for their ability to induce a neovascularization response surrounding the disc after 48 hours. The ability of a neutralizing VEGF antibody to inhibit this response was examined. Results: Active MMPs can initiate an angiogenicresponse in the CAM assay in the form of increasing tortuosity of vessels surrounding the disc. This effect was not observed with pro MMPs. Neutralizing antibodies to VEGF can inhibit this response. In addition, synthetic inhibitor of MMPs can inhibit the angiogenic response of VEGF. Conclusions: Active MMPs can initiate an angiogenic response by increasing the tortuosity of capillaries mediated by release of low levels of VEGF. Our data suggests that MMPs may act upstream as well as downstream of VEGF during in vivo angiogenesis.

Keywords: extracellular matrix • neovascularization • enzymes/enzyme inhibitors