During bone growth, development, and remodeling, angiogenesis as well as osteogenesis are closely associated processes, sharing some essential mediators.
Vascular endothelial growth factor (
VEGF) was initially recognized as the best-characterized endothelial-specific
growth factor, which increased vascular permeability and angiogenesis, and it is now apparent that this
cytokine regulates multiple
biological functions in the endochondral ossification of mandibular condylar growth, as well as long bone formation. The complexity of
VEGF biology is paralleled by the emerging complexity of interactions between
VEGF ligands and their receptors. This narrative review summarizes the family of
VEGF-related molecules, including 7 mammalian members, namely,
VEGF,
placenta growth factor (PLGF), and
VEGF-B, -C, -D, -E, and -F. The
biological functions of
VEGF are mediated by at least 3 corresponding receptors: VEGFR-1/Flt-1, VEGFR-2/Flk-1, VEGFR-3/
Flt-4 and 2 co-receptors of
neuropilin (NRP) and
heparan sulfate proteoglycans (HSPGs). Current findings on endochondral ossification are also discussed, with emphasis on
VEGF-A action in osteoblasts, chondroblasts, and chondroclasts/osteoclasts and regulatory mechanisms involving
oxygen tension, and some
growth factors and
hormones. Furthermore, the therapeutic implications of recombinant
VEGF-A protein therapy and
VEGF-A gene therapy are evaluated. Abbreviations used:
VEGF,
Vascular endothelial growth factor; PLGF,
placenta growth factor; NRP,
neuropilin; HSPGs,
heparan sulfate proteoglycans; FGF,
fibroblast growth factor; TGF,
transforming growth factor; HGF,
hepatocyte growth factor; TNF,
tumor necrosis factor; ECM, extracellular matrix; RTKs,
receptor tyrosine kinases; ERK, extracellular signal
kinases; HIF,
hypoxia-inducible factor.