Proximal aortic aneurysms in mice underexpressing transforming growth factor-β1.

In humans, loss-of-function mutations in multiple component genes of transforming growth factor (TGF)-β signaling have been demonstrated to cause proximal aortic aneurysms. However, association of human variants in the prototype ligand TGFB1 with thoracic aortic aneurysms have not been reported to date. To delineate the consequences of genetically altered Tgfb1 expression on aortic phenotype in mammals, we studied aortic phenotype in mice with loss-of-functions or gain-of-function mutations in Tgfb1 (Tgfb1 and Tgfb1). Tgfb1 mice spontaneously developed proximal aortic aneurysms and had markedly shortened lifespans as compared with wildtype, whereas Tgfb1mice did not develop aortic aneurysms and had comparable lifespans with wildtype. Aortic levels of collagen and elastin stable crosslinks, and the expression of their associated enzymes in Tgfb1 mice were significantly less than those in wildtype. These results suggest that TGF-β1 is protective against aortic aneurysms at least partly via increasing the cross-linking of collagen and elastin.