Augmentation of Lymphangiogenesis by Increased Fluid Channeling in Mouse Skin

描述（由申请人提供）：血管内皮生长因子(VEGF)-C和-D已被证明是淋巴管生成过程中淋巴增殖和迁移所必需的，通过将VEGF -3结合在淋巴内皮细胞上。尽管淋巴管生成的分子调控变得越来越清楚，但对于淋巴管生成过程中淋巴迁移之前的流体通道的形成，以及流体通道的形成是否可以增强，人们所知相对较少。基质金属蛋白酶（MMP）的间质转运形成的流体通道为淋巴管再生提供了支架。在淋巴管形成过程中，淋巴内皮细胞（LECs）最初沿着这些流体通道迁移和增殖，随后组织成成熟的功能性淋巴管。由于流体通道形成先于LEG迁移，流体通道形成的增加导致流体通道密度的增加可能代表了一种增加淋巴管生成的新方法。我们假设过量的MMP与过量的VEGF- C联合使用将通过增加LECs沿流体通道密度增加的增殖和迁移来促进功能性淋巴管生成。我们正在使用最近开发的小鼠模型，其中胶原基质植入物（最初完全没有细胞）取代了小鼠尾部皮肤的一个区域。液体通道形成和新的淋巴生长发生在植入物内部，这可以很容易地识别和区分现有的宿主组织。该项目的主要目的是：1)确定过量MMP在淋巴管生成过程中促进流体通道形成的能力；2)确定在淋巴管生成过程中过量VEGF-C促进淋巴迁移的能力。这项研究的总体目标是提高我们对淋巴管生成的理解，并提供最终有助于替代治疗方法的结果，这种方法可能对患有疾病或干预导致淋巴功能不全的人有效。

DESCRIPTION (provided by applicant): 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.