Abstract 5314: A Critical Role for TGF-β Activity in the Protection Against Aortic Aneurysm Formation and Complications in Adult Mice
Complicated abdominal aortic aneurysm is a major cause of mortality in elderly men. Recent studies unexpectedly showed that increased angiotensin II (AII)-dependent transforming growth factor (TGF)-β activity promotes aortic aneurysm progression in a mouse model of Marfan syndrome. However, the direct role of TGF-β activity in other forms of abdominal aortic aneurysm has not been assessed. Here, we show that systemic neutralization of TGF-β activity using two different antibodies, including the one previously shown to inhibit aneurysm formation in Marfan syndrome, breaks the resistance of normo-cholesterolemic C57BL/6 mice to AII-induced abdominal aortic aneurysm formation and markedly increases their susceptibility to the disease (from ~ 10% to 80–95%, P<0.0001). These aneurysms display a large spectrum of complications on echography, including fissuration, false channel formation and rupture, leading to death from aneurysm complications. The disease and its complications are refractory to inhibition of IFN-γ, IL-4, IL-6 or TNF-α signaling. Genetic deletion of T and B cells or inhibition of CX3CR1 chemokine pathway resulted in partial protection. Interestingly, neutralization of TGF-β activity led to enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, neutralization of TGF-β activity led to substantial increase in MMP-12 activity, and MMP-12 deficiency completely 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 adult normal mice, which contrasts with its reported pathogenic role in Marfan syndrome.