Hedgehog Signaling in Murine Vasculogenesis and Angiogenesis

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Vasculogenesis—the formation of blood vessels de novo from endothelial cells—and angiogenesis—the process of blood vessel remodeling—are regulated by a number of signal transduction pathways, some specific to the vascular system and others used more broadly during embryogenesis. Recent evidence in both zebrafish and mouse suggests a role for Hedgehog (Hh) signaling in both vasculogenesis and angiogenesis. Hh signaling can target endothelial cells directly or can stimulate blood vessel support cells to produce vascular growth factors. Current studies are aimed at determining how the Hh cascade interacts with the other signaling pathways to promote vessel differentiation.

Section snippets

The Hh Pathway

Hh is a secreted signaling molecule that serves multiple roles during embryonic development. The full-length protein is autocatalytically processed to produce the active amino peptide, which is modified by the addition of cholesterol and palmitoyl moieties (Ingham 2001). Release of the Hh signal from the sending cell is facilitated by the membrane protein Dispatched (Ma et al. 2002), and a heparan sulfate proteoglycan is involved in receipt of the signal (Nybakken and Perrimon 2002). The

A Role for Hh Signaling in Vessel Differentiation in the Embryo, Yolk Sac, and Adult

Because Hh signaling plays key roles in pattern formation, differentiation, and proliferation in the early mouse embryo, the vascular system was not initially identified as a target of Hh action when knockout mutants of individual Hh genes were examined. Nonetheless, a role for Hh signaling in blood vessel formation in the embryo is supported by a number of observations, including the hypervascularization of neurectoderm in response to overexpression of Shh (Rowitch et al. 1999) and the

Hh As Part of a Signaling Cascade for Vascular Remodeling Involving Notch and VEGF

How does the Hh signal interact with the other signaling pathways demonstrated to play a role in vascular development? Loss-of-function mutation of a number of genes implicated in angiogenesis results in embryonic vascular remodeling defects. For example, targeted mutation of the Ang1 or Tie2 genes results in severe yolk sac angiogenesis defects by midgestation, reminiscent of the Smo homozygous mutant phenotype (Thurston, 2003, Zhang et al., 2001). This observation suggests that this

Conclusion

Studies point to a role for Hh in blood vessel differentiation. Work in the zebrafish, the mouse yolk sac, and adult vascular injury models suggest that the target of Hh action is not the angioblast cell or endothelial cell, but rather an intermediate cell type that responds to Hh by expressing vascular-specific growth factors such as VEGF. Other studies, which include in vitro work using endothelial cell lines (Kanda et al., 2003, Vokes et al., 2004), are consistent with a direct mode of

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