Transforming Growth Factor β–SMAD2 Signaling and Aortic Arch Development

Molecular processes underlying the remodeling of the symmetric system and the already muscularized pharyngeal arch arteries into an asymmetric aortic arch are slowly becoming unraveled. In normal arch remodeling, selective apoptosis of part of the right dorsal aorta and sixth pharyngeal arch is seen, whereas in the common arch malformations in Tgfβ2 knockout mice, comprising type B interruption and an aberrant right subclavian artery, selective upregulation of apoptosis is additionally found in the left and/or right fourth artery segment. All pharyngeal arch arteries derive transforming growth factor β2-expressing smooth muscle cells from the neural crest. The marked high vulnerability of specifically the fourth arch arteries can be linked to a localized reduced vascular SMAD2 signaling and related expression of fibronectin and neural cell adhesion molecule, providing a link between disturbed arteriogenesis and innervation. The marked correlation between intracardiac and aortic arch malformations in Tgfβ2 mutants can also be understood as a combination of neural crest and flow-related mechanisms. A relation between apoptosis and flow is postulated, in which a role for genes with a shear stress-responsive element, including the endothelially expressed transforming growth factor β1, is implied.