Ascending aorta dilation is a frequent cardiovascular complication of aortic valvular diseases, atherosclerosis, systemic arterial hypertension and genetic disorders. Ascending aorta aneurysms leading to dissections or rupture are major diseases affecting the aorta and are a common cause of premature deaths, such as Marfan syndrome or familial forms of non-syndromic thoracic aortic aneurysm and dissection. No clear explanation for the underlying molecular mechanisms has been found yet, nor is there an effective pharmacological treatment of these diseases. It is of paramount importance that our knowledge of the mediators of the diseases can be improved, so that pharmacological strategies can be designed in order to improve the quality and lifespan of the patients suffering these diseases.
The MERC project seeks to clarify the molecular mechanisms that lead to ascending aorta aneurysms in the conditions mentioned. Previous work by the laboratory established >150 genes highly regulated by angiotensin II in vascular cells. One of such genes, Adamts1, was found to be a major mediator in vascular wall remodeling. Similar to mouse models of Marfan's disease, Adamts1+/- and Adamts1-/- mice present aortic dilation, aneurysms and medial degeneration. Specifically, NOS2 was found to be induced by Adamts1 deficiency.
Based on those results, this project proposed to study the molecular mechanisms mediating these aortic diseases in mice, potentially providing a model for the study of the mechanisms in humans. Thus, the first aim of the project was to better characterize the roles of the isoforms of NOS in Adamts1-defficient mice and the signaling pathways downstream NOS2. A second aim was to determine potential common mechanisms of the aortopathies in Adamts1-defficient mice and Marfan mice, as well as in Marfan patients
