Abstract 12751: Diallyl Trisulfide Augments Lymphangiogenesis via an Akt-Dependent Mechanism and Ameliorates Lymphedema

Abstract

Background: Secondary lymphedema is one of the serious clinical problems that can often occur after surgical resection of malignant tumors. However, no effective treatment options exist at present. Diallyl trisulfide (DATS) is an organic polysulfide found in garlic oil that liberates H2S under physiological conditions. We previously demonstrated that DATS augmented reparative angiogenesis and improved blood perfusion recovery in the HLI model. Here, we investigated the effects of DATS on lymphatic vessel growth and lymphedema in a mouse model and assessed its potential mechanism. Methods and Results: A mouse model of lymphedema was created by ablation of a tail surface lymphatic network, and the tail diameter was measured to estimate lymphedema at day 28 after induction of lymphedema. Lymphatic vessels were detected by immunohistochemical staining as LYVE-1 and podoplanin double-positive cells. The DATS group was intraperitoneally injected with DATS for up to 10 days following lymphedema induction. DATS treated mice (n=10) showed a smaller tail thickness compared with control wild-type (WT) mice (n=11) (p<0.001) which was accompanied by a greater number of lymphatic vessels in the injured tails (p<0.05). Interestingly, the distal lymphatic lumen area was dilated in the control group, whereas the DATS treatment group improve dilated lymphatic area at the distal site of the injured point (p<0.001). In vitro experiments revealed that treatment with DATS promoted the differentiation of human lymphatic endothelial cells (LECs) into tube-like structures (p<0.001) in a dose-dependent manner, when cultured on Matrigel matrix. DATS also stimulated the phosphorylation of Akt in LECs. Furthermore, blockade of Akt activation canceled the DATS-stimulated increase in LEC differentiation. Conclusions: Our data clearly demonstrate that DATS promotes reparative lymphatic vessel growth and ameliorates secondary lymphedema, at least in part, through activation of the Akt pathway within lymphatic endothelial cells.