Pyruvate Kinase M2 Mediates the Glycolysis in the Lymphatic Endothelial Cells and Its Potential Relation to the Progression of Lymphatic Malformations.

Abstract 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 (LECs) and the pathogenesis of lymphatic malformations (LMs) were 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 (HUVECs), while inhibition of PKM2 by shikinon or PKM2 knockdown could significantly suppress glycolysis, migration, tubular formation, and invasion of HDLECs. Moreover, compared with lymphatic vessels in normal skins, PKM2 was highly expressed in lymphatic vessels of LMs and its expression was correlated with infection of LMs. Meanwhile, overexpression of PKM2 in HDLECs could strengthen the proliferation, migration, tubular formation, and invasion of HDLECs. Further experiments in rat LMs models confirmed that targeting PKM2 by shikonin significantly impeded the progression of LMs and even in infected LM rat models. Taken together, these results indicated that PKM2 played a pivotal role in the activation of LECs and promoted the progression of LMs, while inhibition of PKM2 could effectively suppress the pathogenesis of LM lesions in rat model.