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

Abstract

Objective The role of TGF-β signaling in abdominal aortic aneurysm (AAA) formation is controversial. Others reported that systemic blockade of TGF-β by neutralizing antibodies accelerated AAA development in angiotensin II-infused mice. This result is consistent with other studies suggesting that TGF-β signaling prevents AAA. Development of a therapy for AAA that exploits the protective actions of TGF-β would be facilitated by identification of the mechanisms through which TGF-β prevents AAA. We hypothesized that TGF-β 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-β blockade), mice with antibody-mediated systemic neutralization of TGF-β, and mice with genetically based smooth muscle-specific loss of TGF-β signaling. Surprisingly, we found that systemic—but not smooth muscle-specific—TGF-β 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-β 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-β neutralization—significantly accelerated development of aortic pathology, including increased prevalence of intramural hematomas, medial thinning, and adventitial thickening. Conclusion Our results suggest that TGF-β 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.

Contribution of TGF-Beta-Mediated NLRP3-HMGB1 Activation to Tubulointerstitial Fibrosis in Rat With Angiotensin II-Induced Chronic Kidney Disease

“…It is the main effector of the renin angiotensin aldosterone system (RAAS), and increasing its levels can promote RAAS activity, resulting in severe vascular, glomerular, and tubulointerstitial injuries along with the release of the cytokine TGF-beta through the angiotensin type 1 receptor (Balakumar et al, 2019). TGFbeta is required for Ang II to activate fibroblasts and induce fibrosis (Ehanire et al, 2015b;Angelov et al, 2017). In CKD, targeting fibrotic progression may reduce kidney injury and improve the efficiency of treatment strategies based on cellular studies.…”

Inflammation and TGF-β Signaling Differ between Abdominal Aneurysms and Occlusive Disease

“…In contrast, TGF-β-Nab administration exacerbated the pathology of aneurysms in angiotensin-II induced AAA mouse models [63,64]. Consequently, in AAA (dys)regulation of the TGF-β signaling pathway is not clear yet [65]. For example, a small study in 12 AAA and six control biopsies showed downregulation of TβRII subtype mRNA [66].…”

Further Evidence Supporting a Protective Role of Transforming Growth Factor-β (TGFβ) in Aortic Aneurysm and Dissection

“…Addressing this controversial subject in the current issue of ATVB , Angelov et al report that systemic neutralization of TGFβ worsens abdominal but not thoracic aortic disease, whereas conditional deletion of TGFβ signaling in SMCs exacerbates thoracic but not abdominal aortic disease [18]. The findings of this new study by the Dichek group compared to previous studies are summarized in Table 1.…”