Long-term loss of TGF-β signaling in smooth muscle cells of aged adult mice disrupts proximal aortic wall structure and homeostasis

Roles of transforming growth factor β (TGF-β) signaling in smooth muscle cells (SMC) of the adult vasculature remain unclear. In this study, we investigate long-term effects of SMC-specific loss of TGF-β signaling in the aortas of adult mice. Eleven-month-old mice with SMC-specific Cre allele (Acta2-CreERT2) and homozygous floxed type II TGF-β receptor (Tgfbr2) were injected with tamoxifen. Aortas (Acta2-CreERT2 +/0 Tgfbr2 flox/flox; n = 10, 5 males and 5 females) were harvested 16 weeks post-injection and compared with aortas of age-matched control mice (Acta2-CreERT2 0/0 Tgfbr2 flox/flox; n = 10, 5 males and 5 females). There were no grossly observed aortic pathologies or deaths 16 weeks after Tgfbr2 deletion. However, histological examination yet showed significant disruption to aortic wall structure, including aortic dilation, medial thickening, elastolysis, and penetrating aortic ulcers compared to Acta2-CreERT2 0/0 Tgfbr2 flox/flox mice. Furthermore, SMC Tgfbr2 deletion caused macrophage infiltration in the aortic media and collagen accumulation in the tunica adventitia. Long-term loss of TGF-β signaling in aged adult mice does not cause severe aortopathies such as aortic dissection or lethal rupture. However, TGF-β signaling continues to play a critical role in aortic wall homeostasis in adult vasculature. These results caution against proposed therapies that reduce or inhibit TGF-β signaling to prevent or treat aortic diseases in humans.