Endothelial Notch activity promotes angiogenesis and osteogenesis in bone

Blood vessel growth in bone is revealed to require Notch signalling and involve a specialized form of angiogenesis that does not involve endothelial sprouts. Bone growth and vascularization linked There is evidence to suggest that blood vessels, particularly their endothelial cells, control the growth, homeostasis and regeneration of organs. In two papers published in this issue of Nature , Ralf Adams and colleagues demonstrate that the bone vasculature contains endothelial cells specialized to support bone maturation and regeneration. Anjali Kusumbe et al . identify a capillary subtype in the mouse skeletal system that has a key role in mediating bone growth. These vessels contain so-called type H endothelial cells that preferentially associate with osteoprogenitors and are reduced during ageing. Hypoxia-inducible factor 1α (HIF-1α) is shown to be crucial in maintaining the type H cells, and the fact that these cells are lost in aged animals suggests that loss of HIF-1α signalling may be involved in age-related bone changes. In the second paper, Saravana Ramasamy et al . show that blood vessel growth in bone requires Notch signalling and involves a specialized form of angiogenesis that does not involve endothelial sprouts. Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells 1 , 2 . Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours 3 , 4 . Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenet