期刊
STEM CELL RESEARCH & THERAPY
卷 13, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13287-022-02908-x
关键词
Endothelial cell; Angiogenesis; Retinoic acid; Glycometabolism
资金
- National Key R&D Program of China [2021YFA1101902]
- National Natural Science Foundation of China [91949111, 82003756, 81970223]
- Natural Science Foundation of Jiangsu Province [BK20200880, BK20201409]
- Space Medical Experiment Project of China Manned Space Program [HYZHXM01018]
- Jiangsu Province's Key Discipline/Laboratory of Medicine [XK201118]
- National Center for International Research [2017B01012]
- Introduction Project of Clinical Medicine Expert Team for Suzhou [SZYJTD201704]
This study demonstrates that retinoic acid inhibits angiogenesis and suppresses glycolysis in human embryonic stem cell-derived endothelial cells. The inhibitory effect is mediated by upregulation of fructose-1,6-bisphosphatase 1 (FBP1), a key enzyme in gluconeogenesis, and is dependent on the retinoic acid receptor (RAR). These findings suggest that FBP1 may serve as a novel therapeutic target for pathological angiogenesis.
Background Endothelial cells are located in the inner lumen of blood and lymphatic vessels and exhibit the capacity to form new vessel branches from existing vessels through a process called angiogenesis. This process is energy intensive and tightly regulated. Glycolysis is the main energy source for angiogenesis. Retinoic acid (RA) is an active metabolite of vitamin A and exerts biological effects through its receptor retinoic acid receptor (RAR). In the clinic, RA is used to treat acne vulgaris and acute promyelocytic leukemia. Emerging evidence suggests that RA is involved in the formation of the vasculature; however, its effect on endothelial cell angiogenesis and metabolism is unclear. Methods Our study was designed to clarify the abovementioned effect with human embryonic stem cell-derived endothelial cells (hESC-ECs) employed as a cell model. Results We found that RA inhibits angiogenesis, as manifested by decreased proliferation, migration and sprouting activity. RNA sequencing revealed general suppression of glycometabolism in hESC-ECs in response to RA, consistent with the decreased glycolytic activity and glucose uptake. After screening glycometabolism-related genes, we found that fructose-1,6-bisphosphatase 1 (FBP1), a key rate-limiting enzyme in gluconeogenesis, was significantly upregulated after RA treatment. After silencing or pharmacological inhibition of FBP1 in hESC-ECs, the capacity for angiogenesis was enhanced, and the inhibitory effect of RA was reversed. ChIP-PCR demonstrated that FBP1 is a target gene of RAR. When hESC-ECs were treated with the RAR inhibitor BMS493, FBP1 expression was decreased and the effect of RA on angiogenesis was partially blocked. Conclusions The inhibitory role of RA in glycometabolism and angiogenesis is RAR/FBP1 dependent, and FBP1 may be a novel therapeutic target for pathological angiogenesis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据