2012

“TGF-b Signalling in Vascular Smooth Muscle Cells”

$50,000 Funded by TFF
January 2013 - December 2014

George Tellides, MD, PhD

Yale University, New Haven, CT, United States

Marfan syndrome results from a mutation in the gene that encodes for a protein fibrillin-1. It is thought that abnormal fibrillin-1 protein leads to dangerous enlargement, and possible tearing or bursting, of the aorta by enhancing signals from another protein, transforming growth factor (TGF)-β. Current treatment trials in patients with Marfan syndrome are assessing the benefits of drugs which inhibit TGF-β. It is widely believed that the deleterious effects of TGF-β are on the smooth muscle that constitutes the aortic wall. However, the precise effects of overactive TGF-β signaling remain poorly understood. We have investigated the role of TGF-β by using a mouse model in which one of the two receptors (type II receptor) for TGF-β is selectively mutated in smooth muscle after birth. Surprisingly, we found that diminished signaling by TGF-β in aortic smooth muscle lead to spontaneous enlargement and tearing of the aorta and it also worsened disease in Marfan syndrome mice. There are two possible explanations for these unexpected findings. One interpretation is that TGF-β signaling is essential for normal aortic function and that the benefits of inhibiting TGF-β in Marfan syndrome seen by other investigators is due to effects on other types of cells than smooth muscle. An alternative interpretation is that residual or unconventional TGF-β signaling through the remaining normal receptor (type I receptor) in smooth muscle is the cause of disease in our experimental model. We plan to determine which interpretation is correct by breeding mice with mutations in both types of TGF-β receptors (types I and II) that are genetically induced after birth exclusively in smooth muscle (loss of TGF-β receptors before birth or in all cell types leads to death of the embryo within the womb). We will assess signaling pathways by various forms of TGF-β in mutant smooth muscle cells grown in a dish. We will also assess aortic structure and disease in mutant adult mice. The results of our studies will improve our understanding of the role of TGF- β in Marfan syndrome and other causes of aortic aneurysm and dissection. They may impact the application of anti-TGF-β therapy in clinical trials.