Zou Min-Cheng, Yang Yu-Hao, Mao Yun-Peng, Liu Ya, Gao Hui-Bing, Liu Wen-Dong, Liu Jia, Zhang Fu-Yong
Department of Orthopedics, Children's Hospital of Soochow University, Suzhou, China.
Yangliu Central Health Center, Xintai, Shandong, China.
Biochem Genet. 2025 Jul 16. doi: 10.1007/s10528-025-11175-3.
The cartilage of the growth plate is crucial for the longitudinal growth of long bones but is highly susceptible to injury due to its avascular nature. Growth plate injuries frequently result in the formation of a bone bridge, leading to limb length discrepancies and angular deformities. Angiogenesis is a critical factor in the repair process, as new blood vessels deliver oxygen, nutrients, and cellular components essential for bone regeneration. Tie2-expressing macrophages (TEMs) play a pivotal role in promoting angiogenesis in tumors and remodeled tissues; however, their precise function and regulatory mechanisms in epiphyseal plate injury repair remain unclear. This study investigates the role of the VHL/HIF-1α/Tie2/AMPK/Autophagy axis in TEM-mediated angiogenesis. Our findings identify VHL as a key regulator of TEM-driven angiogenesis, where VHL overexpression suppresses, and VHL silencing enhances the pro-angiogenic potential of TEMs. Mechanistically, VHL downregulates HIF-1α, reducing Tie2 surface expression, which in turn modulates AMPK-mediated autophagy. This pathway influences VEGF secretion, thereby promoting endothelial cell proliferation, migration, survival, and tube formation. These findings uncover a novel regulatory mechanism governing TEM-mediated angiogenesis and offer insights into potential therapeutic strategies to enhance vascularization, improve growth plate injury repair, and mitigate long-term orthopedic complications.
生长板软骨对于长骨的纵向生长至关重要，但由于其无血管的特性，极易受到损伤。生长板损伤常导致骨桥形成，进而导致肢体长度差异和角畸形。血管生成是修复过程中的关键因素，因为新血管可输送骨再生所需的氧气、营养物质和细胞成分。表达Tie2的巨噬细胞（TEMs）在促进肿瘤和重塑组织中的血管生成方面起关键作用；然而，它们在骨骺板损伤修复中的精确功能和调控机制仍不清楚。本研究调查了VHL/HIF-1α/Tie2/AMPK/自噬轴在TEM介导的血管生成中的作用。我们的研究结果确定VHL是TEM驱动的血管生成的关键调节因子，其中VHL过表达会抑制，而VHL沉默会增强TEMs的促血管生成潜力。从机制上讲，VHL下调HIF-1α，降低Tie2表面表达，进而调节AMPK介导的自噬。该途径影响VEGF分泌，从而促进内皮细胞增殖、迁移、存活和管形成。这些发现揭示了一种控制TEM介导的血管生成的新调节机制，并为增强血管化、改善生长板损伤修复和减轻长期骨科并发症的潜在治疗策略提供了见解。
