In contrast to how TGF-β signaling drives TAA formation, systemic blockade of TGF-β activity or genetic deletion of its downstream signaling protein SMAD3, a transcriptional modulator and member of TGF-β receptor regulated SMAD family, worsened AngII and CaCl2-induced AAA in mice [113,114]. This evidence concerns the gene TGFB1 and triple-A syndrome.