Retinoic acid inhibits the angiogenesis of human embryonic stem cell-derived endothelial cells by activating FBP1-mediated gluconeogenesis

• Published in: Stem cell research & therapy 2022-06, Vol.13 (1), p.239-239, Article 239
• Main Authors: Yang, Zhuangzhuang, Yu, Miao, Li, Xuechun, Tu, Yuanyuan, Wang, Chunyan, Lei, Wei, Song, Min, Wang, Yong, Huang, Ying, Ding, Fengyue, Hao, Kaili, Han, Xinglong, Ni, Xuan, Qu, Lina, Shen, Zhenya, Hu, Shijun
• Format: Article
• Language: English
• Subjects: Acids; Acne; Acute promyeloid leukemia; Angiogenesis; Antiacne agents; Antibodies; Blood vessels; Cancer; Cardiovascular disease; Cell cycle; Embryonic stem cells; Endothelial cell; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Enzymes; Flow cytometry; Fructose; Gene expression; Gluconeogenesis; Gluconeogenesis - genetics; Glycolysis; Glycometabolism; Human Embryonic Stem Cells - metabolism; Humans; Kinases; Lymphatic system; Metabolism; Metabolites; Neovascularization, Pathologic; Physiological aspects; Promyeloid leukemia; Retinoic acid; Retinoic acid receptors; RNA sequencing; Stem cells; Therapeutic targets; Tretinoin - pharmacology; Vascular endothelial growth factor; Vitamin A
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-022-02908-x

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. Our study was designed to clarify the abovementioned effect with human embryonic stem cell-derived endothelial cells (hESC-ECs) employed as a cell model. 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. The inhibitory role of RA in glycometabolism and angiogenesis is RAR/FBP1 dependent, and FBP1 may be a novel therapeutic target for pathological angiogenesis.