Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Department of Physiology & Pharmacology, Inflammation Research Network, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T6G 2R3, Canada.
Int J Mol Sci. 2024 Jul 17;25(14):7828. doi: 10.3390/ijms25147828.
Secondary lymphedema is caused by damage to the lymphatic system from surgery, cancer treatment, infection, trauma, or obesity. This damage induces stresses such as oxidative stress and hypoxia in lymphatic tissue, impairing the lymphatic system. In response to damage, vascular endothelial growth factor C (VEGF-C) levels increase to induce lymphangiogenesis. Unfortunately, VEGF-C often fails to repair the lymphatic damage in lymphedema. The underlying mechanism contributing to lymphedema is not well understood. In this study, we found that surgery-induced tail lymphedema in a mouse model increased oxidative damage and cell death over 16 days. This corresponded with increased VEGF-C levels in mouse tail lymphedema tissue associated with macrophage infiltration. Similarly, in the plasma of patients with secondary lymphedema, we found a positive correlation between VEGF-C levels and redox imbalance. To determine the effect of oxidative stress in the presence or absence of VEGF-C, we found that hydrogen peroxide (HO) induced cell death in human dermal lymphatic endothelial cells (HDLECs), which was potentiated by VEGF-C. The cell death induced by VEGF-C and HO in HDLECs was accompanied by increased reactive oxygen species (ROS) levels and a loss of mitochondrial membrane potential. Antioxidant pre-treatment rescued HDLECs from VEGF-C-induced cell death and decreased ROS under oxidative stress. As expected, VEGF-C increased the number of viable and proliferating HDLECs. However, upon HO treatment, VEGF-C failed to increase either viable or proliferating cells. Since oxidative stress leads to DNA damage, we also determined whether VEGF-C treatment induces DNA damage in HDLECs undergoing oxidative stress. Indeed, DNA damage, detected in the form of gamma H2AX (γH2AX), was increased by VEGF-C under oxidative stress. The potentiation of oxidative stress damage induced by VEFG-C in HDLECs was associated with p53 activation. Finally, the inhibition of vascular endothelial growth factor receptor-3 (VEGFR-3) activation blocked VEGF-C-induced cell death following HO treatment. These results indicate that VEGF-C further sensitizes lymphatic endothelial cells to oxidative stress by increasing ROS and DNA damage, potentially compromising lymphangiogenesis.
继发性淋巴水肿是由于手术、癌症治疗、感染、创伤或肥胖引起的淋巴系统损伤所致。这种损伤会导致淋巴组织产生氧化应激和缺氧等压力，从而损害淋巴系统。作为对损伤的反应，血管内皮生长因子 C（VEGF-C）水平增加，诱导淋巴管生成。不幸的是，VEGF-C 常常无法修复淋巴水肿中的淋巴损伤。导致淋巴水肿的潜在机制尚不清楚。在这项研究中，我们发现，在小鼠模型中，手术引起的尾巴淋巴水肿在 16 天内增加了氧化损伤和细胞死亡。这与小鼠尾巴淋巴水肿组织中 VEGF-C 水平的增加以及巨噬细胞浸润相对应。同样，在继发性淋巴水肿患者的血浆中，我们发现 VEGF-C 水平与氧化还原失衡之间存在正相关。为了确定在存在或不存在 VEGF-C 的情况下氧化应激的影响，我们发现过氧化氢（HO）诱导人真皮淋巴内皮细胞（HDLEC）中的细胞死亡，而 VEGF-C 增强了这种作用。VEGF-C 和 HO 在 HDLEC 中诱导的细胞死亡伴随着活性氧（ROS）水平的增加和线粒体膜电位的丧失。抗氧化预处理可挽救 HDLEC 免受 VEGF-C 诱导的细胞死亡，并在氧化应激下减少 ROS。正如预期的那样，VEGF-C 增加了存活和增殖的 HDLEC 的数量。然而，在 HO 处理后，VEGF-C 未能增加存活或增殖细胞。由于氧化应激会导致 DNA 损伤，我们还确定了 VEGF-C 处理是否会在经历氧化应激的 HDLEC 中诱导 DNA 损伤。事实上，在氧化应激下，VEGF-C 增加了 DNA 损伤的形式γH2AX（γH2AX）。在 HDLEC 中，VEGF-C 增强了氧化应激损伤，与 p53 激活有关。最后，抑制血管内皮生长因子受体-3（VEGFR-3）的激活阻断了 HO 处理后 VEGF-C 诱导的细胞死亡。这些结果表明，VEGF-C 通过增加 ROS 和 DNA 损伤，进一步使淋巴管内皮细胞对氧化应激敏感，从而可能损害淋巴管生成。
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