School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Medical University, Guangzhou, PR China.
GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, PR China.
J Pathol. 2023 Apr;259(4):388-401. doi: 10.1002/path.6052. Epub 2023 Feb 8.
Switching of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a dedifferentiated (proliferative) phenotype contributes to neointima formation, which has been demonstrated to possess a tumor-like nature. Dysregulated glucose and lipid metabolism is recognized as a hallmark of tumors but has not thoroughly been elucidated in neointima formation. Here, we investigated the cooperative role of glycolysis and fatty acid synthesis in vascular injury-induced VSMC dedifferentiation and neointima formation. We found that the expression of hypoxia-inducible factor-1α (HIF-1α) and its target 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), a critical glycolytic enzyme, were induced in the neointimal VSMCs of human stenotic carotid arteries and wire-injured mouse carotid arteries. HIF-1α overexpression led to elevated glycolysis and resulted in a decreased contractile phenotype while promoting VSMC proliferation and activation of the mechanistic target of rapamycin complex 1 (mTORC1). Conversely, silencing Pfkfb3 had the opposite effects. Mechanistic studies demonstrated that glycolysis generates acetyl coenzyme A to fuel de novo fatty acid synthesis and mTORC1 activation. Whole-transcriptome sequencing analysis confirmed the increased expression of PFKFB3 and fatty acid synthetase (FASN) in dedifferentiated VSMCs. More importantly, FASN upregulation was observed in neointimal VSMCs of human stenotic carotid arteries. Finally, interfering with PFKFB3 or FASN suppressed vascular injury-induced mTORC1 activation, VSMC dedifferentiation, and neointima formation. Together, this study demonstrated that PFKFB3-mediated glycolytic reprogramming and FASN-mediated lipid metabolic reprogramming are distinctive features of VSMC phenotypic switching and could be potential therapeutic targets for treating vascular diseases with neointima formation. © 2023 The Pathological Society of Great Britain and Ireland.
血管平滑肌细胞 (VSMC) 从收缩表型向去分化 (增殖) 表型的转换导致新生内膜形成，新生内膜形成已被证明具有类似肿瘤的性质。葡萄糖和脂质代谢失调被认为是肿瘤的一个标志，但在新生内膜形成中尚未得到充分阐明。在这里，我们研究了糖酵解和脂肪酸合成在血管损伤诱导的 VSMC 去分化和新生内膜形成中的协同作用。我们发现，缺氧诱导因子-1α (HIF-1α)及其靶基因 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 (PFKFB3)，一种关键的糖酵解酶，在人类狭窄颈动脉和钢丝损伤的小鼠颈动脉的新生内膜 VSMC 中表达上调。HIF-1α 的过表达导致糖酵解增加，导致收缩表型降低，同时促进 VSMC 增殖和机械靶蛋白雷帕霉素复合物 1 (mTORC1) 的激活。相反，沉默 Pfkfb3 则产生相反的效果。机制研究表明，糖酵解产生乙酰辅酶 A 以供应从头脂肪酸合成和 mTORC1 激活。全转录组测序分析证实了去分化 VSMC 中 PFKFB3 和脂肪酸合酶 (FASN) 的表达增加。更重要的是，在人类狭窄颈动脉的新生内膜 VSMC 中观察到 FASN 的上调。最后，干扰 PFKFB3 或 FASN 抑制血管损伤诱导的 mTORC1 激活、VSMC 去分化和新生内膜形成。总之，这项研究表明，PFKFB3 介导的糖酵解重编程和 FASN 介导的脂质代谢重编程是 VSMC 表型转换的特征，可能是治疗具有新生内膜形成的血管疾病的潜在治疗靶点。
