PDF(Pubmed)
Abstract：
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 (H2O2) induced cell death in human dermal lymphatic endothelial cells (HDLECs), which was potentiated by VEGF-C. The cell death induced by VEGF-C and H2O2 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 H2O2 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 H2O2 treatment. These results indicate that VEGF-C further sensitizes lymphatic endothelial cells to oxidative stress by increasing ROS and DNA damage, potentially compromising lymphangiogenesis.
摘要：
继发性淋巴水肿是由手术对淋巴系统的损害引起的，癌症治疗,感染,创伤,或者肥胖。这种损伤会引起淋巴组织的氧化应激和缺氧等应激，损害淋巴系统.为了应对损坏，血管内皮生长因子C(VEGF-C)水平升高诱导淋巴管生成。不幸的是,VEGF-C通常不能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诱导的尾部淋巴水肿在16天内增加了氧化损伤和细胞死亡.这对应于与巨噬细胞浸润相关的小鼠尾部淋巴水肿组织中VEGF-C水平的增加。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呈正相关.为了确定存在或不存在VEGF-C时氧化应激的影响，我们发现过氧化氢（H2O2）诱导人真皮淋巴管内皮细胞（HDLECs）的细胞死亡，VEGF-C增强了HDLEC中VEGF-C和H2O2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。抗氧化剂预处理从VEGF-C诱导的细胞死亡中拯救HDLEC，并在氧化应激下减少ROS。不出所料,VEGF-C增加了活的和增殖的HDLEC的数量。然而,H2O2处理后，VEGF-C不能增加活细胞或增殖细胞。由于氧化应激导致DNA损伤,我们还确定了VEGF-C治疗是否会诱导发生氧化应激的HDLECDNA损伤.的确,DNA损伤,以γH2AX(γH2AX)的形式检测，在氧化应激下VEGF-C增加。HDLEC中VEFG-C诱导的氧化应激损伤增强与p53激活有关。最后,血管内皮生长因子受体-3(VEGFR-3)活化的抑制阻断了H2O2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损伤进一步使淋巴内皮细胞对氧化应激敏感，可能危及淋巴管生成。
