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. In this study, blood vessels in the epiphysis-the ends of long bones-retained an unexpected degree of plasticity in adult and even aged mice. With tamoxifen-induced, endothelium-specific deletion of Vegf receptor (Vegfr)-2, the principal mediator of Vegf signaling, marked vascular regression was found in the epiphysis, with growth plate cartilage expansion after epiphyseal ischemia. Consistently, local bone strength was significantly reduced with endothelial Vegfr2 depletion in adult mice. With epiphyseal vascular regression, bone mineral density loss was exacerbated in an ovariectomy-induced mouse model of osteoporosis. Collectively, these findings advance the 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.