Transforming Growth Factor Beta signaling in Marfan Syndrome

Marfan syndrome (MFS) is a genetic disorder associated with development of thoracic aortic aneurysms (TAA). The pathogenesis of MFS is due to mutations in the extracellular matrix (ECM) protein Fibrilin‐1 (Fbn1) that provides structural integrity to the blood vessel and plays an important role in tissue homeostasis by mediating transforming growth factor beta (TGFμ) signaling. Impaired tissue homeostasis due to hyperactivation of TGFμ plays a crucial role in the pathogenesis of this disorder. The purpose of these studies where to elucidate the role of key TGFμ related genes in the pathogenesis of MFS using a well‐characterized MFS animal model, mgR/mgR mice. We show that areas of prominent TAA formation are associated with increased Smad3 phosphorylation as compared to Smad2 phosphorylation. An example of this association is shown by a significant increase of Smad3 dependant PAI‐1 expression at the site of TAA formation. Real time PCR was used to determine gene expression of TGFμ related proteins in 4 sections of the aorta of both Fbn‐1 deficient and WT mice at a young (9–12) and old (12–15) age. We looked at genes related to vascular smooth muscle cell actin, extracellular matrix related proteins and TGFμ signaling proteins to determine in greater detail how hyperactivation of TGFμ relates to blood vessel phenotype and the formation of TAA.