The Regulation of VEGF-C by Interstitial Flow

描述(申请人提供)：血管内皮生长因子(VEGF)-C已被证明是淋巴管生成所必需的，并可用于淋巴引流不足的疾病的淋巴管生成治疗。虽然最近的一些研究报道过表达VEGF-C可以促进淋巴管生成和改善淋巴功能，但我们发现，过量的淋巴生长因子单独促进高于生理水平的功能性淋巴管生长的能力可能是有限的。此外，压缩服装已被证明在临床上显著减少了水肿性人体手臂的肿胀。这些结果表明，通过伤口的间质血流(IF)动力学对于淋巴水肿的缓解可能很重要，并且IF可以在没有事先刺激淋巴生长的情况下在水肿臂增加。因此，直接增加IF的治疗可能对淋巴水肿有益。最近的研究表明，淋巴管生成的早期阶段，液体通道是由间质流动形成的，内源性血管内皮生长因子-C促进淋巴管内皮细胞(LEC)沿液体通道支架的迁移。由于流体通道的形成先于LEC的迁移，并通过依赖IF的基质金属蛋白酶(MMPs)的对流而发生，我们认为通过增强基质金属蛋白酶对流和外源性IF来增强流体通道的形成可能是增加IF和促进功能性淋巴管生成的一种新途径。我们将使用最近开发的小鼠模型，在该模型中，细胞外基质植入(最初完全没有细胞)取代小鼠尾部皮肤的一部分。在种植体内部形成液体通道和新的淋巴管生长，很容易识别并与邻近的宿主组织区分开来。这个模型可以被修改以产生尾部皮肤的淋巴水肿，这将使我们能够测试我们的方法在实验性淋巴水肿中增加IF的能力。公共卫生相关性：血管内皮生长因子-C的间质流动和促淋巴管生成活性可能依赖于液体通道的形成。因此，我们的目标是确定在实验性淋巴水肿中，液体通道形成的增加是否会增加间质流量并促进功能性淋巴管的生成。

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.