1018 – HETEROGENEITY AND FUNCTIONAL SPECIALIZATION OF THE BONE MICROVASCULATURE

Blood vessels in the skeletal system control bone formation and provide niches for hematopoietic stem cells (HSCs). Insight into the architecture and function of the vasculature in the skeletal system was previously limited by the heavily calcified and matrix-rich properties of bone. We have managed to overcome many of these limitations with the help of improved protocols for the processing, immunostaining and live imaging of bone. We found that vascular growth in bone involves a specialized form of angiogenesis that is distinct from other organs. Notch signaling promotes vascular growth in postnatal long bone and thereby osteogenesis. We also discovered that endothelial hypoxia-inducible factor 1α promotes angiogenesis in the postnatal skeletal system, leads to the amplification of osteoprogenitor cells and improves bone formation.Aging is associated with a loss of bone mass and reduced HSC functionality. Our work has uncovered extensive age-related changes in the bone vasculature, which involve alterations in arteries, blood flow, perivascular cells, and capillary EC subpopulations. These changes are associated with a strong reduction in endothelial Notch signaling and, remarkably, EC-specific reactivation of the Notch pathway in aged mice triggers increases in bone formation and HSC niches. EC subpopulations are also critical for regeneration following lethal irradiation and bone marrow transplantation.