Hedgehog signaling induces arterial endothelial cell formation by repressing venous cell fate

Abstract

In vertebrate embryos, the dorsal aorta and the posterior cardinal vein form in the trunk to comprise the original circulatory loop. Previous studies implicate Hedgehog (Hh) signaling in the development of the dorsal aorta. However, the mechanism controlling specification of artery versus vein remains unclear. Here, we investigated the cell-autonomous mechanism of Hh signaling in angioblasts (endothelial progenitor cells) during arterial-venous specification utilizing zebrafish mutations in Smoothened (Smo), a G protein-coupled receptor essential for Hh signalling. smo mutants exhibit an absence of the dorsal aorta accompanied by a reciprocal expansion of the posterior cardinal vein. The increased number of venous cells is equivalent to the loss of arterial cells in embryos with loss of Smo function. Activation of Hh signaling expands the arterial cell population at the expense of venous cell fate. Time-lapse imaging reveals two sequential waves of migrating progenitor cells that contribute to the dorsal aorta and the posterior cardinal vein, respectively. Angioblasts deficient in Hh signaling fail to contribute to the arterial wave; instead, they all migrate medially as a single population to form the venous wave. Cell transplantation analyses demonstrate that Smo plays a cell-autonomous role in specifying angioblasts to become arterial cells, and Hh-signaling depleted angioblasts differentiate into venous cells instead. Collectively, these studies suggest that arterial endothelial cells are specified and formed via repressing venous cell fate at the lateral plate mesoderm by Hh signaling during vasculogenesis.

Molecular identification of venous progenitors in the dorsal aorta reveals an aortic origin for the cardinal vein in mammals

“…Supporting this theory, the DA and CV emerge by direct migration of two separate sources of progenitor cells in two independent waves from the lateral plate mesoderm (Williams et al, 2010;Kohli et al, 2013). However, it has also been reported that the CV forms via segregation from the DA (Herbert et al, 2009).…”

Assembly and patterning of the vascular network of the vertebrate hindbrain

“…The patterning of the trunk vasculature in the zebrafish is directed by a number of different cues. Signaling from midline structures is necessary for primary vascular patterning of the trunk dorsal aorta and cardinal vein (Zhong et al, 2000;Zhong et al, 2001;Lawson et al, 2003;Hong et al, 2006;Swift and Weinstein, 2009;Williams et al, 2010), whereas positive and negative somite-derived molecules subsequently regulate the angiogenic growth of trunk intersegmental and parachordal vessels (Torres-Vazquez et al, 2004;Pollard et al, 2006;Wilson et al, 2006;Jones and Li, 2007). These and other recent findings point to the important role of locale-specific patterning mechanisms for blood vessels.…”

Arterial-venous network formation during brain vascularization involves hemodynamic regulation of chemokine signaling

“…Furthermore, VEGF signaling has been shown to act upstream of the Notch pathway during arterial differentiation . A more recent report also suggests a direct involvement of the Hedgehog pathway in arterial differentiation (Williams et al, 2010). Thus, Sonic hedgehog, VEGF and Notch are necessary for proper arterial gene expression and the separation of arteries and veins.…”