Role of hypoxia-inducible factor-1alpha in angiogenic-osteogenic coupling.

Angiogenesis and osteogenesis are tightly coupled during bone development and regeneration. The vasculature supplies oxygen to developing and regenerating bone and also delivers critical signals to the stroma that stimulate mesenchymal cell specification to promote bone formation. Recent studies suggest that the hypoxia-inducible factors (HIFs) are required for the initiation of the angiogenic-osteogenic cascade. Genetic manipulation of individual components of the HIF/vascular endothelial growth factor (VEGF) pathway in mice has provided clues to how coupling is achieved. In this article, we review the current understanding of the cellular and molecular mechanisms responsible for angiogenic-osteogenic coupling. We also briefly discuss the therapeutic manipulation of HIF and VEGF in skeletal repair. Such discoveries suggest promising approaches for the development of novel therapies to improve bone accretion and repair.