VHL Suppresses Angiogenesis Through HIF-1a-Mediated Ang/Tie2/AMPK/VEGF Signaling Pathway in Tie-2 Expressed Macrophages (TEMs).

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.