Glycolysis and de novo fatty acid synthesis cooperatively regulate pathological vascular smooth muscle cell phenotypic switching and neointimal hyperplasia

Author:

Cao Kaixiang1,Zhang Tiejun23,Li Zou1,Song Mingchuan1,Li Anqi1,Yan Jingwei1,Guo Shuai1,Wang Litao14,Huang Shuqi1,Li Ziling1,Hou Wenzhong5,Dai Xiaoyan6,Wang Yong7,Feng Du1,He Jun8,Fu Xiaodong13ORCID,Xu Yiming13ORCID

Affiliation:

1. School of Basic Medical Sciences The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Medical University Guangzhou PR China

2. 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

3. State Key Laboratory of Respiratory Disease Guangzhou Medical University Guangzhou PR China

4. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital, Fudan University Shanghai PR China

5. Department of Cerebrovascular Disease The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital Qingyuan PR China

6. School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou PR China

7. College of Basic Medicine Chengdu University of Traditional Chinese Medicine Chengdu Sichuan PR China

8. Department of Rehabilitation Center The First Affiliated Hospital of Guangzhou University of Chinese Medicine Guangzhou PR China

Abstract

AbstractSwitching 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.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Guangdong Province

Publisher

Wiley

Subject

Pathology and Forensic Medicine

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