Inflammatory Pathways in Aortic Aneurysms



 DESCRIPTION (provided by applicant): AAAs are age-associated localized dilations of the abdominal aorta that expand over the years and frequently lead to aortic rupture with a mortality rate as high as 90 %. Importantly, AAAs are one of the few cardiovascular disorders for which there is no pharmacological therapy. The only available treatment is surgical repair of the aortic wall, an expensive and risky procedure that is not a valid option for patients with small AAAs. Thus, the lack of a drug that prevents or slows down AAA growth represents an important unmet clinical need, which highlights the need for a precise knowledge of the molecular mechanisms underlying this vascular condition. It is widely accepted that the primary events in AAA development involve inflammation and proteolytic degradation of extracellular matrix in the vessel wall. We recently reported the existence of a new signaling axis that involves non-canonical Wnt signaling modulators and controls the inflammatory response in the adipose tissue micro-environment. Specifically, we identified Sfrp5 as a new anti-inflammatory adipokine, which antagonizes the pro-inflammatory activity of Wnt5a, a regulator of non-canonical Wnt signaling. Our recently published studies have combined the analysis of human fat specimens and the characterization of novel genetic mouse models to show that Sfrp5/Wnt5a signaling is a regulator of adipose tissue inflammation and systemic metabolic health. However, the endocrine actions of Sfrp5 and the direct contribution of this non- canonical Wnt signaling axis to inflammatory conditions independent of obesity remain to be demonstrated. In this regard, the expression patterns of Sfrp5 and Wnt5a suggest an important role of these molecules in vascular inflammatory disorders in general and AAAs in particular. Sfrp5 is highly expressed in adipose tissue, but severely downregulated by aging (as well as obesity). Conversely, Wnt5a is expressed at high levels in the abdominal aorta and markedly upregulated in human and mouse AAAs. Based on these findings, we propose to test the hypothesis that the aberrant regulation of the Sfrp5/Wnt5a axis represents a previously unrecognized insult to the aortic wall that contributes to vascular inflammation and AAA development. Additionally, given the urgent need for drugs that prevent AAA growth and rupture, we also aim to evaluate whether Wnt5a-inhibitory strategies are effective at preventing the growth of pre-established experimental AAAs. The specific aims of this project are: 1. To investigate the role of the Sfrp5/Wnt5a regulatory axis in experimental abdominal aortic aneurysm formation. 2. To investigate the role of the Wnt5a co-receptors Ror1 and Ror2 in experimental abdominal aortic aneurysm formation. 3. To evaluate the therapeutic potential of Wnt5a-inhibitory strategies in the setting of experimental abdominal aortic aneurysms