Dimorphic Effects of Transforming Growth Factor-β Signaling During Aortic Aneurysm Progression in Mice Suggest a Combinatorial Therapy for Marfan Syndrome

Abstract

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.

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…Studies conducted in MFS mouse models have suggested that effects of TGF-b signaling attenuation with neutralizing antibodies are dependent on the developmental stage of the vessel wall, with early TGF-b inhibition, between three and six weeks of age, being deleterious, and late TGF-b inhibition, after 6 weeks of age, being beneficial (Cook et al 2015). These observations are consistent with the studies discussed above suggesting that TGF-b signaling has a protective role prenatally and perinatally, when it is required to complete vessel wall development and elastogenesis, and a pathogenic role after such events are completed.…”

Cytokine amplification and macrophage effector functions in aortic inflammation and abdominal aortic aneurysm formation

“…Results of this study provide important new information for our understanding of the role that both systemic and localized tissue inflammation play in these life threatening pathologies of the aortic vessel wall. In addition, results of this and other studies (23) point to significant differences in mechanisms of aortic dissection linked to genetic diseases such as Marfan syndrome, in which TGFβ and its downstream intracellular signaling molecules Smad2/3 and ERK1/2, have important, causal roles in the vessel wall dissections (24,25).…”

Insights into ascending aortic aneurysm pathogenesis using in vivo and ex vivo imaging systems in angiotensin II-infused mice

“…It is worth noting that the outer laminae orientation of ascending aortic pathology is not a unique feature in Ang II-infused mice. This feature has been frequently observed in many animal models in which ascending aortic aneurysmal diseases are provoked by a wide variety of stimuli (7,(15)(16)(17). Of clinical relevance, the predominance of pathology in the outer medial layers is also a common feature in human ascending aortic aneurysm and dissection (14,18).…”

“…Although there are multiple genetic disruptions that lead to ascending aortic aneurysms and dissection, these diseases can be mimicked by manipulations in animal models. It is worth noting that angiotensin II (Ang II) and its type 1 (AT1) receptor activation contribute to the development and progression of ascending aortic pathologies in all of these animal models (2)(3)(4)(5)(6)(7). Ascending aortic aneurysms are one risk factor for aortic dissection.…”