Vascular endothelial growth factors (VEGF)-C and -D have been shown to be necessary for lymphatic proliferation and migration during lymphangiogenesis by binding VEGFR-3 on lymphatic endothelial cells. Although the molecular regulation of lymphangiogenesis is becoming more clear, relatively little is known about the formation of fluid channels, a process that precedes lymphatic migration during lymphangiogenesis, or whether fluid channel formation is amenable to augmentation. Fluid channels, formed by interstitial transport of Matrix Metalloprotease (MMP), provide a scaffold within which lymphatic vessels regenerate. During lymphangiogenesis lymphatic endothelial cells (LECs) initially migrate and proliferate along these fluid channels, and subsequently organize into mature functional lymphatic vessels. Because fluid channel formation precedes LEG migration, an augmentation of fluid channel formation leading to an increased density of fluid channels may represent a novel approach for augmenting lymphangiogenesis. We hypothesize that administration of excess MMP in combination with excess VEGF- C will promote functional lymphangiogenesis by increasing the proliferation and migration of LECs along an increased density of fluid channels. We are using a recently developed mouse model where a collagen matrix implant (initially entirely devoid of cells) replaces a region of mouse tail skin. Fluid channel formation and new lymphatic growth occur inside the implant, which can be easily identified and distinguished from existing host tissue. The major aims of this project are to 1) determine the ability of excess MMP to enhance the formation of fluid channels during lymphangiogenesis; 2) determine the ability of excess VEGF-C to promote lymphatic migration during lymphangiogenesis. The overall goal of this research is to improve our understanding of lymphangiogenesis and provide results that will ultimately contribute to an alternative therapeutic approach that may be efficacious in people who suffer from diseases of or interventions resulting in lymphatic insufficiency. ? ? ?
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