VEGF: an essential mediator of both angiogenesis and endochondral ossification

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.