The Regulation of Interstitial Flow in Experimental Lymphedema by Compression

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。我们还发现，实验性淋巴水肿在没有淋巴管生成的情况下能够消退。在临床上，加压服装已被证明可以显著减少水肿性手臂的肿胀。这些结果表明，通过梗阻部位的间质血流(IF)动力学对于淋巴水肿的缓解可能是重要的，并且IF可以在没有预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，在淋巴管生成的早期阶段，IF和内源性的VEGF-C促进淋巴管内皮细胞(LEC)沿流体通道支架迁移，从而形成流体通道。我们假设，通过增加流体通道的形成，压缩负荷可能会增加，联合使用VEGF-C治疗和压缩负荷可能会通过通过流体通道传递VEGF-C和建立指导功能性淋巴管生长的VEGF-C梯度来改善功能性淋巴管的生成。我们的目标是确定是否通过增加流体通道的形成来增加压缩负荷，通过加压与外源性VEGF-C蛋白一起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能增加。 公共卫生相关性：乳腺癌手术后腋窝淋巴结清扫后通常会出现淋巴水肿。虽然压迫疗法可以减轻淋巴水肿，但其作用机制尚不清楚。我们的目的是阐明压迫在调节间质血流中的作用，并确定压迫/淋巴管生成联合治疗改善淋巴水肿的能力。

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.