Study reveals how DKK3 triggers smooth muscle cell transformation in aortic aneurysm

Background

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder that primarily affects elderly males. It often develops asymptomatically, yet aneurysm rupture can lead to rapid fatality. Currently, no effective pharmacological therapies are available to halt or reverse AAA progression. Previous studies have highlighted the phenotypic switching of vascular smooth muscle cells (VSMCs) as a central event in AAA pathogenesis, although the molecular mechanisms governing this process remain incompletely understood. Notably, the secreted glycoprotein DKK3 has recently been associated with multiple cardiovascular diseases, where it influences tissue regeneration and upregulates matrix metalloproteinases (MMPs). However, the potential role and mechanistic contribution of DKK3 in AAA had not yet been elucidated.

Research progress

In order to observe the changes of DKK3 during AAA developmen t and to elucidate its functional role and underlying mechanisms, the teams of Associate Prof. Baoqi Yu, Prof. Aijuan Qu from the Basic Medical College of Capital Medical University and Prof. Qingbo Xu from The First Affiliated Hospital, Zhejiang University School of Medicine started an in-depth cooperation. The researchers identified a shift in VSMC subpopulations in AAA, characterized by a decline in contractile VSMCs and an expansion of modulated VSMCs exhibiting high DKK3 expression. DKK3 was markedly upregulated in aortic aneurysm tissues and was predominantly localized within VSMCs.

In an angiotensin II (Ang II)-induced mouse model of AAA, both systemic DKK3 knockout and VSMC-specific DKK3 knockdown markedly attenuated aortic dilation, reduced the incidence and rupture rates of AAA, and suppressed elastin degradation. Mechanistically, DKK3 deficiency maintained the contractile phenotype of VSMCs, downregulated MMP expression, and enhanced VSMC contractility. Furthermore, DKK3 knockout reversed Ang II-induced suppression of the TGF-β signaling pathway, elevated TGFβ3 expression, and promoted Smad2/3 phosphorylation. Further investigation revealed that DKK3 modulates the TGF-β-Smad2/3 signaling pathway through the transcription factor ATF6. ATF6 knockdown increased TGFβ3 level and VSMC contractile markers, whereas treatment with the ATF6 agonist AA147 counteracted the effects of DKK3 deficiency and promoted VSMC phenotype switching.

This study demonstrates that DKK3 promotes AAA progression through TGFβ3-Smad2/3 signaling pathway mediated with ATF6, driving VSMC phenotype switching toward a synthetic state, enhancing MMP production, and accelerating elastin degradation. These findings identify DKK3 as a potential therapeutic target for maintaining VSMC homeostasis in AAA.

Future prospects

Current clinical management of AAA relies primarily on surgical intervention, with no effective drug therapies available to reverse disease progression. This study elucidates a novel mechanism by which DKK3 promotes AAA through the ATF6-TGFβ3-Smad2/3 axis, regulating VSMC phenotypic transformation. Inhibition or blockade of DKK3 may therefore represent a promising therapeutic strategy for AAA. These results not only advance our understanding of AAA pathogenesis but also suggest DKK3 as a potential diagnostic biomarker and therapeutic target.