Abstract 290: Noncanonical Wnt Signaling Contributes to Angiotensin II-Induced Vascular Inflammation and Abdominal Aortic Aneurysm Formation

Abstract

Background: Abdominal aortic aneurysms (AAA) are life-threatening localized dilations of the abdominal aorta. A precise knowledge of the molecular mechanisms underlying this disease is required, especially because there are no validated drugs for its treatment. Wnt proteins are secreted signaling molecules that play fundamental roles during embryo development and in the adult. There are 19 Wnt family members in mammals, which frequently have overlapping or redundant functions. Wnt5a is a particularly unique Wnt protein that induces non-canonical Wnt signaling and appears to modulate innate immunity and several signaling pathways involved in vascular inflammation. However, its role in the development of macrovascular pathologies remains unexplored. HYPOTHESIS. Wnt5a-mediated non-canonical Wnt signaling contributes to vascular inflammation and AAA development. METHODS: Cre-loxP strategies were used to generate whole-body Wnt5a-deficient mice, myeloid- Wnt5a-deficient mice and myeloid Wnt5a-overexpressing mice. AAAs were induced in these mouse strains in an apolipoprotein E deficient (apoE-KO) or wild-type (apoE-WT) background by Angiotensin II (Ang II) infusion. Ultrasonography was used to evaluate AAA progression. AAA samples were harvested for histology and gene expression analysis. RESULTS. Whole-body ablation of Wnt5a inhibited Ang II-induced vascular inflammation and AAA formation in apoE-KO mice. Myeloid-specific Wnt5a ablation reduced AAA size, incidence rate and severity, suggesting that myeloid cells are a significant source of pathogenic Wnt5a. Conversely, myeloid-restricted Wnt5a-overexpression led to rapid formation and rupture of dissecting AAAs in Ang II-infused apoE-KO and apoE-WT mice. In human AAAs, Wnt5a expression is significantly increased both at the transcript and protein levels. Mechanistically, Wnt5a appears to promote AAA formation at least in part by promoting vascular inflammation and extracellular matrix remodeling via augmented recruitment of immune cells to the vessel wall. CONCLUSION: Wnt5a-mediated non-canonical Wnt signaling plays a major role in inflammatory AAA formation and may be a potential target for novel AAA therapies.