Elevated Dickkopf 3 Promotes Abdominal Aortic Aneurysm Formation via Modulated Phenotype Switch of Vascular Smooth Muscle Cells.

Abstract

Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease with no effective therapeutic intervention. Vascular smooth muscle cell (VSMC) phenotypic switching and elevated matrix metalloproteinase (MMP) levels are key pathogeneses of AAA, although the underlying regulatory mechanisms remain to be fully elucidated. In our study, single-cell RNA-sequencing data analysis demonstrated a substantial elevation in modulated VSMCs in patients with aortic aneurysm, accompanied by Dickkopf 3 (DKK3) up-regulation. Both systemic DKK3 knockout and VSMC-specific DKK3 knockdown led to a marked decrease in both the incidence and mortality of AAA in mice. Reintroduction of DKK3 in Dkk3 ^-/- Apoe ^-/- mice via adeno-associated virus (AAV) exacerbated AAA development. DKK3 deficiency maintained the contractile phenotype of VSMC and inhibited MMP production. Given the critical role of TGF-β signaling in VSMC phenotypic switching and the progression of AAA, its regulatory mechanisms exhibit spatiotemporal heterogeneity, and the precise underlying mechanisms require further investigation. Next, we aim to investigate the regulators of this pathway. Mechanistically, DKK3 deficiency activates the TGFβ3-Smad2/3 signaling pathway by down-regulating ATF6, thereby inhibiting VSMC phenotype switching. In summary, these findings indicate that DKK3 drives the phenotypic transition of VSMCs to a synthetic phenotype through the ATF6-TGFβ3-Smad2/3 signaling pathway during the development of AAA, which represents a potential target for therapeutic intervention to maintain VSMC homeostasis in AAA.