Augmentation of Lymphangiogenesis by Increased Fluid Channeling in Mouse Skin

描述（由申请方提供）：已证明血管内皮生长因子（VEGF）-C和-D通过结合淋巴管内皮细胞上的VEGFR-3，在淋巴管生成期间对淋巴增殖和迁移是必需的。虽然淋巴管生成的分子调控正变得越来越清楚，但对流体通道的形成知之甚少，这是淋巴管生成过程中淋巴管迁移之前的一个过程，或者流体通道的形成是否适合于增强。由基质金属蛋白酶（MMP）的间质转运形成的流体通道提供了淋巴管再生的支架。在淋巴管生成过程中，淋巴管内皮细胞（LEC）最初沿着这些流体通道沿着迁移和增殖，随后组织成成熟的功能性淋巴管。因为流体通道形成先于LEG迁移，所以导致流体通道密度增加的流体通道形成的增强可能代表用于增强淋巴管生成的新方法。我们假设过量MMP与过量VEGF-C联合给药将通过增加LEC的增殖和沿着增加的流体通道密度的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区域。液体通道形成和新的淋巴管生长发生在植入物内，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增强流体通道形成的能力; 2）确定过量VEGF-C在淋巴管生成过程中促进淋巴管迁移的能力。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，该方法可能对患有淋巴功能不全疾病或导致淋巴功能不全的干预措施的人有效。

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.