Sonic hedgehog (Shh) is a morphogen controlling the skeletal and vascular development in the embryo but is also reactivated during adult repair processes. Thus, this molecule holds great therapeutic potential for biotechnological and biomedical approaches aiming to enhance tissue regeneration or to replace damaged tissues. According to present knowledge, Shh signaling controls the expression of several families of growth factors involved in neovascularization and vessel maturation and acts upstream of the most prominent angiogenic growth factor, vascular endothelial growth factor. In this context, a very interesting feature of Shh is that it controls both angiogenic activity and vessel stabilization by mural cells. In parallel, Shh seems to have a direct effect on endothelial cell tube formation and seems to trigger the differentiation process of mesenchymal stem cells toward the osteogenic lineage. In this chapter, we will therefore shortly summarize the multifaceted potential of Shh for bone repair and vascularization according to the current literature. In addition, we will show how coculture models based on outgrowth endothelial cells and primary osteoblasts can be used to reveal some of the relevant mechanisms by which Shh drives and connects bone regeneration and vascularization.
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