Supplement for Sheppard: Adventitial-Medial Interactions in Thoracic Aortic Diseases

The major goal of the parent grant is to understand the molecular mechanisms of thoracic aortic aneurysms and dissection mediated by cell (smooth muscle cells from two embryonic origins of the aortic wall)-to-cell (fibroblasts in the adventitia of the aortic wall) interactions. Multiple mouse models were proposed to explore related mechanisms including two well-established Marfan mouse models that pathologies identified in patients and one mouse model that was developed by my mentor, Dr. Daugherty, the PI of the parent grant. In the research project I proposed, I will use one Marfan mouse model as proposed in Dr. Daugherty’s grant that I have characterized with Dr. Daugherty’s help. A cardinal feature of Marfan syndrome is localized elastin fragmentation in the ascending aorta that portends aortic dilation and rupture. There is now a focus on the role of the renin angiotensin system in Marfan aortopathy. This was initiated by the demonstration that losartan, an angiotensin II type 1 receptor (AT1R) blocker, attenuated aortic root expansion in a Marfan syndrome mouse model with fibrillin-1 haploinsufficiency. My planned research proposes to test a hypothesis that elastin degradation in ascending aortic aneurysms is associated with pERK 1/2 and pSMAD2 mediated protease activation that can be attenuated by AT1R blockade and AT2R stimulation.