The Regulation of VEGF-C by Interstitial Flow

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DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF)-C has been shown to be necessary forlymphangiogenesis and may be useful for lymphangiogenic therapy in diseases of inadequate lymphatic drainage. Although a number of recent studies have reported that overexpression of VEGF-C can promote lymphangiogenesis and improve lymphatic function, we have found that the ability of excess lymphatic growth factor alone to increase functional lymphatic growth above physiological levels may be limited. Furthermore, compressive garments have been shown to produce clinically significant reductions in the swelling of the edematous human arm. These results suggest that interstitial flow (IF) dynamics across the wound may be important for resolution of lymphedema and that IF can be increased in the edematous arm without prior stimulation of lymphatic growth. Therefore therapies that directly increase IF may be beneficial for lymphedema. It has recently been demonstrated that fluid channels are formed by interstitial flow and that endogenous VEGF-C promotes lymphatic endothelial cell (LEC) migration along the fluid channel scaffold during early stages of lymphangiogenesis. Because formation of fluid channels precedes LEC migration and occurs by IF dependent convection of matrix metalloproteinases (MMPs), we believe that an augmentation of fluid channel formation by enhanced MMP convection with exogenous IF may represent a novel approach for increasing IF and promoting functional lymphangiogenesis. We will use a recently developed mouse model where an extracellular 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 neighboring host tissue. This model can be modified to produce lymphedema of the tail skin, which will allow us to test the ability of our approaches to increase IF in experimental lymphedema. PUBLIC HEALTH RELEVANCE: Both interstitial flow and the pro-lymphangiogenic activity of vascular endothelial growth factor-C may be dependent upon fluid channel formation. Therefore, we aim to determine whether an augmentation of fluid channel formation will increase interstitial flow and promote functional lymphangiogenesis in experimental lymphedema.