Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF

Abstract

Bone is a highly vascularized tissue, but the function of angiogenesis in bone modeling and remodeling is still poorly defined, and the molecular mechanisms that regulate angiogenesis in bone are only partially elucidated. Genetic manipulations in mice have recently highlighted the critical role of the hypoxia-inducible-factor/vascular endothelial growth factor pathway in coupling angiogenesis and osteogenesis. In this brief perspective, we review the current understanding of the mechanisms responsible for this coupling. Elucidation of such mechanisms will expand our knowledge of bone development and homeostasis, and it may aid in the design of new therapies for accelerating bone regeneration and repair.

FIG. 1

Regulation of osteogenesis-angiogenesis coupling by HIF and VEGF. Mature osteoblasts located on the bone surface express HIFs and respond to HIF activation, which may be induced in response to low oxygen tensions in the bone and marrow environment. Cell-autonomous effects of HIF may affect bone formation (osteogenesis), but a critical effect of HIF stabilization in mature osteoblasts is the increased accumulation of VEGF. VEGF can act through its receptors (VEGFR) on endothelial cells to induce angiogenesis and thereby indirectly increase the supply of oxygen and nutrients required for osteogenesis. Increased vascularization may also lead to a higher input of putative skeletal stem cells and/or (pre)osteoblasts and to elevated levels of endothelium-derived osteogenic growth factors or anabolic signals. In addition, VEGF can affect osteogenesis through direct interactions with osteoblasts that also express VEGF receptors. Altogether, the HIF–VEGF pathway is likely to be critically important in coupling the processes of angiogenesis and osteogenesis.