TGF-β (Transforming Growth Factor-β) Signaling Protects the Thoracic and Abdominal Aorta From Angiotensin II-Induced Pathology by Distinct Mechanisms

Objective-The role of TGF-beta (transforming growth factor-beta) signaling in abdominal aortic aneurysm (AAA) formation is controversial. Others reported that systemic blockade of TGF-beta by neutralizing antibodies accelerated AAA development in angiotensin II-infused mice. This result is consistent with other studies suggesting that TGF-beta signaling prevents AAA. Development of a therapy for AAA that exploits the protective actions of TGF-beta would be facilitated by identification of the mechanisms through which TGF-beta prevents AAA. We hypothesized that TGF-beta signaling prevents AAA by its actions on aortic medial smooth muscle cells. Approach and Results-We compared the prevalence, severity, and histopathology of angiotensin II-induced AAA among control mice (no TGF-beta blockade), mice with antibody-mediated systemic neutralization of TGF-beta, and mice with genetically based smooth muscle-specific loss of TGF-beta signaling. Surprisingly, we found that systemic-but not smooth muscle-specific TGF-beta blockade significantly increased the prevalence of AAA and tended to increase AAA severity, adventitial thickening, and aortic wall macrophage accumulation. In contrast, abdominal aortas of mice with smooth muscle-specific loss of TGF-beta signaling differed from controls only in having a thinner media. We examined thoracic aortas of the same mice. Here we found that smooth muscle-specific loss of Tgfbr2- but not systemic TGF-beta neutralization-significantly accelerated development of aortic pathology, including increased prevalence of intramural hematomas, medial thinning, and adventitial thickening. Conclusion-Our results suggest that TGF-beta signaling prevents both abdominal and thoracic aneurysmal disease but does so by distinct mechanisms. Smooth muscle extrinsic signaling protects the abdominal aorta and smooth muscle intrinsic signaling protects the thoracic aorta.