Han Fei, Simeroth Summer, Zhu Jie, Gryniuk Irma, Pranay Atul, Chen Weiqing, Wang Yuan, Cai Yuanyuan, Shen Zhiyuan, Wang Guangyu, Griffin Courtney T, Xia Lijun, Yu Pengchun
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Dev Cell. 2025 May 2. doi: 10.1016/j.devcel.2025.04.012.
The lymphatic vasculature comprises lymphatic capillaries and collecting vessels. To support lymphatic development, lymphatic endothelial cells (LECs) utilize nutrients to fuel lymphangiogenic processes. Meanwhile, LECs maintain constant prospero homeobox 1 (PROX1) expression critical for lymphatic specification. However, molecular mechanisms orchestrating nutrient metabolism while sustaining PROX1 levels in LECs remain unclear. Here, we show that loss of RAPTOR, an indispensable mechanistic target of rapamycin complex 1 (mTORC1) component, downregulates PROX1 and impairs lymphatic capillary growth and differentiation of collecting lymphatics in mice. Mechanistically, mTORC1 inhibition in mouse and human LECs causes Myc reduction, which decreases hexokinase 2 (HK2) and glutaminase (GLS), inhibiting glycolysis and glutaminolysis. Myc or HK2/GLS ablation impedes lymphatic capillary and collecting vessel formation. Interestingly, mTORC1 regulation of PROX1 is independent of Myc-HK2/GLS signaling. Moreover, genetic interaction analysis indicates that Myc and PROX1 play crucial roles in mTORC1-regulated lymphatic development. Collectively, our findings identify mTORC1 as a key regulator of metabolic programs and PROX1 expression during lymphangiogenesis.
淋巴脉管系统由毛细淋巴管和集合淋巴管组成。为了支持淋巴管发育，淋巴管内皮细胞（LEC）利用营养物质来促进淋巴管生成过程。同时，LEC维持对淋巴管特化至关重要的prospero同源框1（PROX1）的持续表达。然而，在维持LEC中PROX1水平的同时协调营养物质代谢的分子机制仍不清楚。在此，我们表明，雷帕霉素复合物1（mTORC1）不可或缺的组成部分RAPTOR的缺失会下调PROX1，并损害小鼠的毛细淋巴管生长和集合淋巴管的分化。从机制上讲，对小鼠和人LEC的mTORC1抑制会导致Myc减少，进而降低己糖激酶2（HK2）和谷氨酰胺酶（GLS），抑制糖酵解和谷氨酰胺分解。Myc或HK2/GLS的缺失会阻碍毛细淋巴管和集合淋巴管的形成。有趣的是，mTORC1对PROX1的调节独立于Myc-HK2/GLS信号传导。此外，基因相互作用分析表明，Myc和PROX1在mTORC1调节的淋巴管发育中起关键作用。总之，我们的研究结果确定mTORC1是淋巴管生成过程中代谢程序和PROX1表达的关键调节因子。
