The Regulation of Interstitial Flow in Experimental Lymphedema by Compression

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，可能对淋巴引流不足疾病的淋巴管生成治疗有用。虽然最近的一些研究报道了VEGF-C的过表达可以促进淋巴管生成和改善淋巴功能，但我们发现仅过量的淋巴生长因子将功能性淋巴生长提高到生理水平以上的能力可能有限。我们还发现，实验性淋巴水肿能够在没有淋巴管生成的情况下解决。临床上，压缩服装已被证明产生显著减少肿胀的人的手臂水肿。这些结果表明，通过阻塞部位的间质流动（IF）动力学可能对淋巴水肿的解决很重要，并且IF可以在没有事先刺激淋巴生长的情况下在水肿臂中增加。因此，直接增加IF的治疗可能对淋巴水肿有益。最近有研究表明，液体通道是由IF形成的，内源性VEGF-C在淋巴管形成的早期阶段促进淋巴内皮细胞（LEC）沿着液体通道支架迁移。我们假设压缩负荷可能通过增加流体通道的形成来增加IF，并且将VEGF-C治疗与压缩负荷相结合可能通过通过流体通道对流VEGF-C和建立可以指导功能性淋巴生长的VEGF-C梯度来改善功能性淋巴管生成。我们的目的是确定压缩负荷是否可以通过增加流体通道的形成来增加IF，通过与外源性VEGF-C蛋白结合的压缩来增加流体通道是否可以增强功能性淋巴管生成和改善淋巴水肿，以及相对于静态压缩负荷，循环压缩负荷是否可以增加IF。

DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF)-C has been shown to be necessary for lymphangiogenesis 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. We have also found that experimental lymphedema is able to resolve in the absence of lymphangiogenesis. Clinically, compressive garments have been shown to produce significant reductions in the swelling of the edematous human arm. These results suggest that interstitial flow (IF) dynamics across the obstruction site 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 IF and that endogenous VEGF-C promotes lymphatic endothelial cell (LEC) migration along the fluid channel scaffold during early stages of lymphangiogenesis. We hypothesize that compressive loading may increase IF by increasing fluid channel formation and that combining VEGF-C therapy with compressive loading may improve functional lymphangiogenesis by convecting VEGF-C through fluid channels and establishing VEGF-C gradients that can direct functional lymphatic growth. We aim to determine whether compressive loading may increase IF by increasing the formation of fluid channels, whether an augmentation of fluid channels by compression in conjunction with exogenous VEGF-C protein may enhance functional lymphangiogenesis and improve lymphedema, and whether cyclic compressive loading may increase IF relative to static compressive loading. PUBLIC HEALTH RELEVANCE: Lymphedema often follows axillary lymph node dissection from breast cancer surgery. Although compression therapy reduces lymphedema, the mechanism of action is not clear. We aim to clarify the role of compression in regulating interstitial flow and to determine the ability of combined compression/lymphangiogenesis therapy to improve lymphedema.