Abstract Body: Aortic aneurysm (AA) is characterized by the degeneration of the extracellular matrix, leading to aortic dilation. Its asymptomatic progression results in high mortality rates, and currently, there are no effective pharmacotherapies available. CCN1 is a secreted matricellular protein that exerts diverse activities across cell types via multiple integrin receptors. Our preliminary data indicate that CCN1 is upregulated in the lesion areas of an Angiotensin II (Ang II)-induced AA mouse model.
Vascular smooth muscle cell (VSMC) reprogramming is a critical factor in maintaining vessel integrity and driving AA development. We hypothesized that CCN1 mediates AA progression by inducing VSMCs to adopt a degradative phenotype via the integrin α6β1. To test this, Apoe^-/- mice carrying an α6β1-binding-deficient CCN1 mutant (Ccn1-dm) were subjected to an Ang II-induced AA model. Following a 4-week Ang II infusion, Apoe^-/-Ccn1^dm/dm mice exhibited significantly reduced aortic dilation, smaller maximal diameters, and preserved lumen size compared to Apoe^-/-Ccn1^+/+ controls. Furthermore, the mutant group maintained better aortic wall integrity with reduced macrophage infiltration.
Mechanistically, we utilized the antagonistic peptide T1 to block N1-α6β1 binding in rat primary aortic VSMCs. Western blotting revealed that Ang II induces the expression of CNN1, KLF4, MMP12, and IL-6. Blocking CCN1 signaling with T1 inhibited the induction of KLF4, a known initiator of VSMC dedifferentiation, and suppressed degradative phenotype markers. While the precise mechanism by which CCN1/α6β1 axis regulates KLF4 remains to be determined, our results demonstrate that CCN1 promotes matrix remodeling and VSMC phenotypic switching through α6β1 binding. Consequently, CCN1 represents a promising novel therapeutic target for AA.