Institute of Mechanobiology and Medical Engineering, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Minhang, Shanghai 200240, China.
Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2023 Feb 7;120(6):e2219630120. doi: 10.1073/pnas.2219630120. Epub 2023 Jan 30.
Endothelial progenitor cells (EPCs) play an important role in vascular repair and re-endothelialization after vessel injury. EPCs in blood vessels are subjected to cyclic stretch (CS) due to the pulsatile pressure, but the role of CS in metabolic reprogramming of EPC, particularly its vascular homing and repair, is largely unknown. In the current study, physiological CS applied to EPCs at a magnitude of 10% and a frequency of 1 Hz significantly promoted their vascular adhesion and endothelial differentiation. CS enhanced mitochondrial elongation and oxidative phosphorylation (OXPHOS), as well as adenosine triphosphate production. Metabolomic study and Ultra-high performance liquid chromatography-mass spectrometry assay revealed that CS significantly decreased the content of long-chain fatty acids (LCFAs) and markedly induced long-chain fatty acyl-CoA synthetase 1 (Acsl1), which in turn facilitated the catabolism of LCFAs in mitochondria via fatty acid β-oxidation and OXPHOS. In a rat carotid artery injury model, transplantation of EPCs overexpressing Acsl1 enhanced the adhesion and re-endothelialization of EPCs in vivo. MRI and vascular morphology staining showed that Acsl1 overexpression in EPCs improved vascular repair and inhibited vascular stenosis. This study reveals a mechanotransduction mechanism by which physiological CS enhances endothelial repair via EPC patency.
内皮祖细胞（EPCs）在血管损伤后的血管修复和再内皮化中发挥重要作用。由于脉动压力，血管中的 EPC 会受到循环拉伸（CS）的影响，但 CS 在 EPC 代谢重编程中的作用，特别是其血管归巢和修复作用，在很大程度上尚不清楚。在本研究中，幅度为 10%、频率为 1 Hz 的生理 CS 显著促进了 EPC 的血管黏附和内皮分化。CS 增强了线粒体伸长和氧化磷酸化（OXPHOS）以及三磷酸腺苷的产生。代谢组学研究和超高效液相色谱-质谱分析表明，CS 显著降低了长链脂肪酸（LCFAs）的含量，并显著诱导了长链脂肪酸辅酶 A 合成酶 1（Acsl1），从而通过脂肪酸β-氧化和 OXPHOS 促进了线粒体中 LCFAs 的分解代谢。在大鼠颈动脉损伤模型中，过表达 Acsl1 的 EPC 移植增强了 EPC 在体内的黏附和再内皮化。MRI 和血管形态学染色显示，EPC 中 Acsl1 的过表达改善了血管修复并抑制了血管狭窄。这项研究揭示了一种机械转导机制，即生理 CS 通过 EPC 通畅性增强内皮修复。
