Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor-β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.MFS is a systemic disorder of connective tissue caused by mutations in FBN1, the gene encoding fibrillin-1 (1). As a principal component of the extracellular matrix microfibril (2, 3), fibrillin-1 was initially thought to play primarily a structural role in connective tissue. Several lines of evidence support an additional role as a regulator of the cytokine TGF-β (4, 5). Mice homozygous for a hypomorphic Fbn1 allele have impaired pulmonary alveolar septation associated with increased TGF-β signaling that can be prevented by perinatal administration of a polyclonal TGF-β neutralizing antibody (NAb) (5). Similarly, myxomatous

Objective Studies of mice with mild Marfan syndrome (MFS) have correlated the development of thoracic aortic aneurysm (TAA) with improper stimulation of non-canonical (Erk-mediated) TGFβ signaling by the angiotensin type I receptor (AT1r). This correlation was largely based on comparable TAA modifications by either systemic TGFβ neutralization or AT1r antagonism. However, subsequent investigations have called into question some key aspects of this mechanism of arterial disease in MFS. To resolve these controversial points, here we made a head-to-head comparison of the therapeutic benefits of TGFβ neutralization and AT1r antagonism in mice with progressively severe MFS (Fbn1mgR/mgR mice). Approach and Results Aneurysm growth, media degeneration, aortic levels of phosphorylated Erk and Smad proteins and the average survival of Fbn1mgR/mgR mice were compared after a ∼3 month long treatment with placebo and either the AT1r antagonist losartan or the TGFβ neutralizing antibody 1D11. In contrast to the beneficial effect of losartan, TGFβ neutralization either exacerbated or mitigated TAA formation depending on whether treatment was initiated before (post-natal day 16; P16) or after (P45) aneurysm formation, respectively. Biochemical evidence related aneurysm growth with Erk-mediated AT1r signaling, and medial degeneration with TGFβ hyperactivity that was in part AT1r-dependent. Importantly, P16-initiated treatment with losartan combined with P45-initiated administration of 1D11 prevented death of Fbn1mgR/mgR mice from ruptured TAA. Conclusions By demonstrating that promiscuous AT1r and TGFβ drive partially overlapping processes of arterial disease in MFS mice, our study argues for a therapeutic strategy against TAA that targets both signaling pathways while sparing the early protective role of TGFβ.