Deposition of collagen type I onto skeletal endothelium reveals a new role for blood vessels in regulating bone morphology

Abstract

In recent years, blood vessels have been shown to be involved in morphogenesis of various organs. The vasculature is also known to be essential for endochondral bone development; yet, the underlying mechanism has remained elusive. Here, we show that a unique composition of blood vessels facilitates a role of the endothelium in bone mineralization and morphogenesis. Immunostaining and electron microscopy showed that the endothelium in developing bones lacks basement membrane, which normally isolates the vessel from its surroundings. Further analysis revealed the presence of collagen type I, secreted by osteoblasts, on the endothelial wall of these vessels. Because collagen type I is the main component of the osteoid, which serves as a template for mineral deposition during endochondral ossification, we hypothesized that the bone vasculature guides the formation of the collagenous template and consequently of the mature bone. Indeed, analysis showed that some of the bone vessels undergo mineralization. Moreover, the vascular pattern at each embryonic stage prefigured the mineral distribution pattern observed one day later. Finally, perturbation of vascular patterning by overexpressing Vegf in osteoblasts resulted in abnormal bone morphology, supporting a role of blood vessels in bone morphogenesis. Together, these data reveal the unique composition of the endothelium in developing bones and indicate that vascular patterning plays a role in determining bone shape by forming a template for deposition of bone matrix.