Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone, Nature

Abstract

The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass. Blood vessels mediate the transport of circulating cells, oxygen, nutrients and waste products, but also provide so-called angiocrine signals controlling organ growth and homeostasis In the mammalian skeletal system, growth of the vascular network is regulated by signals provided by chondrocytes and other bone cells, among which the vascular endothelial growth factor (VEGF) is best understood Vessel architecture and bone oxygenation Previous work has shown that molecular and structural differences distinguish arteries and distal arterioles in bone from sinusoidal capillaries Identification of a distinct EC subpopulation in bone In addition to revised immunofluorescence protocols, we visualized bone vessels by endothelial-cell-specific expression of green fluorescent protein (GFP) in tamoxifen-treated Cdh5(PAC)-CreERT2, Rosa26-mT/mG double transgenic mic