State Key Laboratory Breeding Base of Basic Science of Stomatology (HUbei-MOST) & Key Laboratory of Oral Biomedicine, Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Oral & Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Department of Pathology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Am J Pathol. 2021 Jan;191(1):204-215. doi: 10.1016/j.ajpath.2020.10.003. Epub 2020 Oct 29.
Metabolism plays a pivotal role in the formation of the lymphatic vasculature. Pyruvate kinase M2 (PKM2) is typically a metabolic marker of proliferating cells and maintains the growth of vascular endothelial cells. In this study, the potential status of PKM2 in lymphatic endothelial cells and the pathogenesis of lymphatic malformations (LMs) was investigated. The glycolysis index, including glucose uptake, ATP, and lactate production, stayed at a relatively high level in human dermal lymphatic endothelial cells (HDLECs) compared with human umbilical vein endothelial cells, whereas the inhibition of PKM2 by shikonin or PKM2 knockdown significantly suppressed glycolysis, migration, tubular formation, and invasion of HDLECs. Moreover, compared with lymphatic vessels in healthy skin, lymphatic vessels of LMs expressed PKM2 highly, and this expression correlated with infection of LMs. Meanwhile, the overexpression of PKM2 in HDLECs strengthened the proliferation, migration, tubular formation, and invasion of HDLECs. The findings from further experiments in a rat LM model support that targeting PKM2 by shikonin significantly impedes the progression of LMs, even in an infected LM rat model. Taken together, these results indicate that PKM2 plays a pivotal role in the activation of LECs and promotes the progression of LMs, whereas the inhibition of PKM2 can effectively suppress the pathogenesis of LM lesions in the rat model.
代谢在淋巴管形成中起着关键作用。丙酮酸激酶 M2（PKM2）通常是增殖细胞的代谢标志物，维持血管内皮细胞的生长。在这项研究中，研究了 PKM2 在淋巴管内皮细胞中的潜在状态以及淋巴管畸形（LM）的发病机制。与脐静脉内皮细胞相比，人皮肤淋巴管内皮细胞（HDLECs）的糖酵解指数（包括葡萄糖摄取、ATP 和乳酸生成）保持在相对较高的水平，而通过紫草素或 PKM2 敲低抑制 PKM2 显著抑制 HDLECs 的糖酵解、迁移、管状形成和侵袭。此外，与健康皮肤中的淋巴管相比，LM 中的淋巴管高表达 PKM2，这种表达与 LM 的感染相关。同时，在 HDLECs 中过表达 PKM2 可增强 HDLECs 的增殖、迁移、管状形成和侵袭。在大鼠 LM 模型中的进一步实验结果表明，通过紫草素靶向 PKM2 可显著抑制 LM 的进展，即使在感染的 LM 大鼠模型中也是如此。综上所述，这些结果表明 PKM2 在 LEC 的激活中起关键作用，并促进 LM 的进展，而抑制 PKM2 可有效抑制大鼠模型中 LM 病变的发病机制。
