Plasticity of blood vessels and its role in bone homeostasis in the adult epiphysis

Loss of vascular endothelial growth factor (VEGF) signaling profoundly impairs vascular growth during development. In contrast, once established in adulthood, blood vessels become largely quiescent and less dependent on VEGF signaling, providing the rationale for the clinical use of VEGF inhibitors to selectively target tumor angiogenesis. Here, we show that blood vessels in the epiphysis-the ends of long bones-retain an unexpected degree of plasticity in adult and even aged mice. Tamoxifen-inducible, endothelial-specific deletion of VEGF receptor 2 (Vegfr2), the principal mediator of VEGF signaling, induced marked vascular regression in the epiphysis and led to growth plate cartilage expansion following epiphyseal ischemia. Consistently, endothelial Vegfr2 deletion in adult mice significantly reduced local bone strength. Moreover, epiphyseal vascular regression exacerbated bone mineral density loss in an ovariectomy-induced mouse model of osteoporosis. Collectively, these findings advance our understanding of angiogenic-osteogenic coupling in adulthood and provide a mechanistic framework for the vulnerability of the femoral head and neck to fractures in the elderly.