AbstractsBiology & Animal Science

Osteogenesis and angiogenesis are tightly coupled during bone formation and repair. Blood vessels not only carry oxygen and nutrients to the developing bone, but also play an active role in bone formation and remodeling by mediating the interaction between osteoblasts, osteocytes, osteoclasts and vascular cells at a variety of levels. Tissue hypoxia is believed to be a major stimulus for angiogenesis. Hypoxia activates the hypoxia- inducible factor (HIF) pathway and triggers hypoxia-responsive gene expression such as vascular endothelial growth factor (VEGF), which plays a critical role in angiogenesis, endochondral bone formation and bone repair following fracture. In this dissertation, I investigated the mechanisms through which osteoblasts use the HIF pathway to sense reduced oxygen tension and transmit signals that impinge on angiogenic and osteogenic gene programs during bone formation. Using a genetic approach, I have demonstrated that overexpression of HIF in mouse osteoblasts through disruption of the von Hippel-Hindau (pVHL)-mediated degradation pathway results in profound increases in angiogenesis and osteogenesis which appear to be mediated by cell nonautonomous mechanisms involving VEGF. Based on these results, the role of the HIF pathway during bone repair was also investigated by using a murine model of distraction osteogenesis in which repair is accomplished through osteoblast-mediated new bone formation. Mice with overexpressed HIF, through either deletion of Vhl gene or treatment of prolyl hydroxylase inhibitors, showed a markedly increased vascularity and accelerated bone regeneration in response to distraction osteogenesis. The increased bone regeneration in Vhl mutant mice was eliminated by concomitant infusion of VEGF receptor antibodies, suggesting that VEGF is required for bone regeneration. These findings suggest that the HIF/VEGF pathway also plays an important role in coupling angiogenesis and bone formation during repair. The precise mechanism for angiogenicosteogenic coupling during skeletal development, as to what extent VEGF functions independent of endothelial cells, is currently under investigation. 1 online resource (x, 110 p. : ill., digital, PDF file) Pharmacology and Toxicology; Joint Health Sciences; bone angiogenesis VEGF HIF repair UNRESTRICTED