Abstract 587: The Matricellular Protein Ccn1 Induces Aortic Aneurysms In Mice

Abstract

Aortic aneurysm ( AA ) is a dilation of the aorta due to an arterial wall weakening. Chronic inflammation and oxidative stress have been associated with dysregulated vascular smooth muscle cell (VSMC) homeostasis and functional phenotype leading to loss of VSMCs, matrix remodeling, and AA formation. The matricellular protein CCN1 (cellular communication network factor 1) has been identified in a subpopulation of VSMCs at the early stage of phenotypic switching. To assess the involvement of CCN1 in AA, CCN1 expression was examined in the CaCl 2 -induced mouse AA model using Ccn1 lacZ/+ -knockin mice. CCN1 expression revealed by whole-mount aortic X-gal staining was intensely induced 3 days after the peri-aortic application of CaCl 2 and sustained more refined to the lesion areas. CCN1 was largely expressed in VSMCs and infiltrating macrophages. CCN1 binds to its receptor integrin α6β1 and promotes atherogenesis through prolonged elevations of inflammation, oxidative stress, and matrix remodeling, the similar driving forces underlying AA progression. To test the role of CCN1 in AA development, Ccn1 dm/dm mice, carrying the α6β1-binding-defective mutant allele Ccn1-dm , were tested in the mouse AA model. Ccn1 dm/dm mice exhibited remarkable resistance against CaCl 2 -induced AA comparing with wild-type control mice 4 weeks after treatment. The Ccn1 dm/dm aortic wall possessed well-structured elastic lamellae and organized VSMC layers with less infiltrating macrophages, inflammation (interleukin-1β and tumor necrosis factor-α), and oxidative stress (8-OHdG). MMP9 levels detected by immunostaining were induced by CaCl 2 in the wild-type aortic wall, but not detected in Ccn1 dm/dm mice. Together, our results demonstrate a critical role of CCN1 in AA formation through binding its receptor α6β1 to increase VSMC inflammation and oxidative stress. CCN1 can be used as a novel therapeutic target for AA.