TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II–infused mice

Abstract

Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II-dependent TGF-β activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-β in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-β activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II-induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-γ, IL-4, IL-6, or TNF-α signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-β activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-β neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-β in the taming of the innate immune response and the preservation of vessel integrity in C57BL/6 mice, which contrasts with its reported pathogenic role in Marfan syndrome.

The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels

“…21 After a longer diabetes duration, normalized Tgf-b signaling may also limit basement membrane thickening. However, the data from the models of aortic aneurysms 32 and aortic stenosis, 13 combined with our Figure 8 Diabetes and SM16 synergistically alter morphology and density of the retinal capillary network. A: Representative images of retinal trypsin digests, stained using the Lendrum Picro-Mallory method for fibrin, showing normal morphology and density in control rats (C), control rats treated for 3 weeks with SM16 (CþSM16), and diabetic rats with 7 months of diabetes untreated (D), but abnormal vessel morphology, geometry, and density in diabetic rats with 7 months of diabetes treated with SM16 for 3 weeks (DþSM16).…”

“…In an angiotensin IIeinduced mouse model of abdominal aortic aneurysm, the aneurysm-prone segment showed increased Tgf-b expression, 31 and systemic neutralization of the Tgf-b activity markedly accelerated the progression of the aneurysm and its complications. 32 In a mouse model of aortic stenosis and heart failure induced by aortic banding, there was increased Tgf-b signaling, and treatment with SM16ddespite reducing myocardial fibrosis and ameliorating functiondeventually accelerated the death of the mice by causing aortic rupture at the banded site. 13 The investigators of both studies concluded that intervening against the increased Tgf-b signaling attenuated a protective response.…”

T lymphocytes and aortic aneurysms

“…Systemic inhibition of TGF-β failed to protect mice from AAA formation and rupture, associated with increased accumulation of macrophages and T lymphocytes, great loss of SMCs and enhanced degradation of elastin. The up-regulation of MMP-12 activity in anti-TGF-β treated mice also contributed to aneurysm formation [59]. Overexpression of TGF-β in hearts of ApoE  transgene mice showed less T cell infiltration, more collagen, reduced inflammatory cytokines and MMP-13, as well as increased metalloproteinase-2, with suppression of aneurysm formation [60].…”

Rôle du TGFβ dans un modèle d’anévrisme de l’aorte abdominale chez la souris

“…Nous avons montré que l'injection répétée d'anticorps bloquants anti-TGF chez des souris traitées par angiotensine II induisait des anévrismes de l'aorte abdominale chez 100 % des animaux avec des complications mortelles chez 70 % d'entre eux [6]. Les complications visualisées à l'échographie et confirmées par l'examen histologique post-mortem comportent des dissections 3 avec ou sans faux chenal 3 La dissection est une déchirure de la paroi artérielle avec une porte d'entrée par laquelle le sang sous pression s'engouffre et participe au décollement des feuillets de la paroi ; ceci peut aboutir à la formation d'une poche de sang circulant dans la paroi même de l'artère, appelée faux chenal et séparée donc du vrai chenal (ou lumière du vaisseau) par le bout de paroi décollée (appelée flap).…”

“…Nous avons montré que l'injection répétée d'anticorps bloquants anti-TGF chez des souris traitées par angiotensine II induisait des anévrismes de l'aorte abdominale chez 100 % des animaux avec des complications mortelles chez 70 % d'entre eux [6]. Les complications visualisées à l'échographie et confirmées par l'examen histologique post-mortem comportent des dissections 3 avec ou sans faux chenal et des ruptures rétropéritonéales.…”