The Regulation of VEGF-C by Interstitial Flow

间质流对 VEGF-C 的调节

• 批准号: 7515846
• 负责人: Jeremy Goldman
• 金额: $ 23.4万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7515846
• 关键词: Cell Proliferation; Cells; Convection; Data; Disease; Distal; Drainage procedure; Endothelial Cells; Extracellular Matrix; Goals; Growth; Growth Factor; Human; Implant; Injury; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Capillaries; Lymphatic Endothelial Cells; Lymphedema; Matrix Metalloproteinases; Mediating; Modeling; Mus; Natural regeneration; Numbers; Physiological; Protein Overexpression; Public Health; Regulation; Reporting; Resolution; Skin; Staging; Swelling; Tail; Testing; Tissues; Upper arm; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; angiogenesis; cell motility; clinically significant; improved; interstitial; mouse model; novel strategies; scaffold; wound

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.

描述（由申请人提供）：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疾病的淋巴管生成治疗。尽管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，但我们发现单独过量的淋巴生长因子增加功能性淋巴生长超过生理水平的能力可能是有限的。 此外，压缩服装已被证明产生临床显着减少肿胀的水肿人arm. These结果表明，间质流（IF）动力学的伤口可能是重要的解决水肿和IF可以增加在水肿的手臂没有事先刺激淋巴生长。因此，直接增加IF的治疗可能对水肿有益。最近已经证明，流体通道由间质流动形成，并且在淋巴管生成的早期阶段，内源性VEGF-C促进淋巴管内皮细胞（LEC）沿流体通道支架沿着迁移。由于流体通道的形成先于LEC迁移，并发生IF依赖性对流的基质金属蛋白酶（MMPs），我们认为，增强流体通道的形成，增强MMP对流与外源性IF可能代表一种新的方法，增加IF和促进功能性淋巴管生成。我们将使用最近开发的小鼠模型，其中细胞外基质植入物（最初完全没有细胞）取代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并与邻近的宿主组织区分开来。可以修改该模型以产生尾部皮肤的水肿，这将允许我们测试我们的方法在实验性水肿中增加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流体通道的形成。因此，我们的目的是确定是否增加液体通道的形成将增加间质流量，并促进功能性淋巴管生成实验性水肿。

项目成果

Nitric oxide leads to cytoskeletal reorganization in the retinal pigment epithelium under oxidative stress.

• DOI: 10.4236/abb.2012.38143
• 发表时间: 2012
• 期刊: Advances in bioscience and biotechnology (Print)
• 作者: Sripathi SR;He W;Um JY;Moser T;Dehnbostel S;Kindt K;Goldman J;Frost MC;Jahng WJ
• 通讯作者: Jahng WJ