Marfan Syndrome (MFS) is an autosomal dominant disorder of the connective tissue with major manifestations in the ocular, skeletal and cardiovascular systems. The underlying cause is mutations in fibrillin-1, a glycoprotein component of the extracellular matrix. While a multisystemic disease, the main source of morbidity and mortality is progressive aortic root dilatation leading to dissection and subsequent death from aortic rupture.

Recently, a role for increased TGF-beta activation and signaling has been implicated by the Dietz lab as the driving force behind disease pathogenesis in MFS. To develop our understanding of the specific TGF-beta signaling pathways involved, we interrogated the role of Smads (intracellular effectors of canonical TGF-beta signaling) in disease pathogenesis by introducing haploinsufficiency for the positive regulator, Smad4, in a mouse model of Marfan Syndrome. In doing so, we identified a role for canonical TGF-beta signaling within the muscular and pulmonary systems.

Paradoxically, we found that Smad4 haploinsufficiency in the context of MFS results in a synthetic lethal phenotype with death by aortic rupture. This led to further investigation into the role of non-canonical TGF-beta signaling in the pathogenesis of disease. Mitogen activated protein kinase (MAPK) activation was identified as an integral player in the development of aortic pathology in MFS. Antagonism of either extracellular related kinases (ERK1/2) or Jun N-terminal Kinases (JNK1/2) led to rescue of aortic root growth in MFS mice. Additionally, JNK antagonism improved aortic wall architecture, reduced ascending aortic growth and prevented death in Smad4 haploinsufficient MFS mice. Taken together, our results suggest that upregulation of MAPK signaling contributes to vascular disease in MFS and represents a target for therapeutic intervention.