TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II–infused mice
Yu Wang, … , Alain Tedgui, Ziad Mallat
Yu Wang, … , Alain Tedgui, Ziad Mallat
Published January 25, 2010
Citation Information: J Clin Invest. 2010;120(2):422-432. https://doi.org/10.1172/JCI38136.
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Research Article

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.

Authors

Yu Wang, Hafid Ait-Oufella, Olivier Herbin, Philippe Bonnin, Bhama Ramkhelawon, Soraya Taleb, Jin Huang, Georges Offenstadt, Christophe Combadière, Laurent Rénia, Jason L. Johnson, Pierre-Louis Tharaux, Alain Tedgui, Ziad Mallat

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Figure 2

Two-dimensional color-coded ultrasound imaging of aortic aneurysm development and complications in mice.

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Two-dimensional color-coded ultrasound imaging of aortic aneurysm develo...
(A) Two-dimensional (2D) ultrasound imaging of a normal abdominal aorta visualized between the left (top) and the right (bottom) kidneys. (B) 2D color-coded Doppler imaging revealed a fusiform dilation of the upper renal abdominal aorta. M-mode showed increased diastolic and systolic diameters (C). (D–F) Dissected aneurysm of the upper renal abdominal aorta. Color-coded Doppler imaging revealed a dissection with 2 lumens: the true lumen was coded in red and showed a forward blood flow toward the renal arteries and the suprarenal abdominal aorta; the second lumen, colored in blue, showed a backward blood flow (D). Pulsed Doppler revealed an accelerated forward blood flow in the true lumen (E) and a backward blood flow in the second lumen (F), which was suggestive of false channel formation. (G–I) Complete disintegration of the distal part of an aortic aneurysm (G). 2D color-coded Doppler imaging evidenced the inferior limit of the aneurysm just upstream of the emergence of the right renal artery coded in blue (H). Targeted M-mode is shown in I. (J) Histograms show determination of vessel diameter in vivo using ultrasound imaging at day 0 and day 15 after the beginning of treatment. Vessel dilatation at the suprarenal level was markedly pronounced in the mice that received anti–TGF-β antibody (n = 7 for Ang II and n = 17 for Ang II + anti-TGF-β). We also found a significant dilatation of the ascending aorta at day 15 in the anti–TGF-β group (n = 7–9 per group).