Study shows how DKK3 triggers smooth muscle cell transformation in aortic aneurysms

Study shows how DKK3 triggers smooth muscle cell transformation in aortic aneurysms

background

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease that primarily affects older men. It often develops asymptomatically, but an aneurysm rupture can quickly lead to death. There are currently no effective pharmacological therapies available to halt or reverse the progression of AAA. Previous studies have highlighted the phenotypic switch of vascular smooth muscle cells (VSMCs) as a central event in AAA pathogenesis, although the molecular mechanisms controlling this process are still incompletely understood. In particular, the secreted glycoprotein DKK3 has recently been linked to several cardiovascular diseases, where it influences tissue regeneration and upregulates matrix metalloproteinases (MMPs). However, the possible role and mechanistic contribution of DKK3 in AAA were not yet clear.

Research progress

To observe the changes of DKK3 during AAA development and 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 of Zhejiang University School of Medicine began an intensive collaboration. The researchers noted a shift in VSMC subpopulations in AAA, characterized by a decline in contractile VSMCs and an expansion of modulated VSMCs with high DKK3 expression. DKK3 was significantly upregulated in aortic aneurysm tissues and predominantly localized in VSMCs.

In an angiotensin II (Ang II)-induced mouse model of AAA, both systemic DKK3 knockout and VSMC-specific DKK3 knockdown significantly attenuated aortic dilatation, 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 increased VSMC contractility. Furthermore, DKK3 knockout reversed Ang II-induced suppression of TGF-β signaling, increased 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. Knockdown of ATF6 increased TGFβ3 levels and VSMC contractile markers, whereas treatment with the ATF6 agonist AA147 counteracted the effects of DKK3 deficiency and promoted VSMC phenotype switching.

This study shows that DKK3 promotes AAA progression through the ATF6-mediated TGFβ3-Smad2/3 signaling pathway, thereby switching the VSMC phenotype to a synthetic state, increasing MMP production, and accelerating elastin degradation. These results identify DKK3 as a potential therapeutic target for maintaining VSMC homeostasis in AAA.

Future prospects

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

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