Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease that primarily affects elderly men. It often develops asymptomatically, but aneurysm rupture can lead to rapid death. Currently, there are no effective pharmacological therapies to halt or reverse AAA progression; current clinical management of AAA relies primarily on surgery. Prevention is merely directed toward the management of high blood pressure. Previous studies have highlighted vascular smooth muscle cell (VSMC) phenotypic switching as a central event in AAA pathogenesis, although the molecular mechanisms governing this process remain incompletely understood.
In particular, the secreted glycoprotein DKK3 has recently been associated with multiple cardiovascular diseases, where it influences tissue regeneration and upregulates matrix metalloproteinases (MMPs). DKK3 (Dickkopf-3) is a secreted protein involved in various biological processes, such as embryonic development and modulation of the tumor microenvironment. Depending on the cellular context, it can act as an oncogene or a tumor suppressor. Researchers identified 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 markedly upregulated in aortic aneurysm tissue and was predominantly localized within cells. In an angiotensin II (Ang II)-induced mouse model of AAA, both systemic DKK3 knockout and VSMC-specific DKK3 knockdown significantly suppressed elastin degradation, attenuated aortic dilation and reduced the incidence and rates of AAA rupture. Mechanistically, DKK3 deficiency maintained the contractile phenotype of VSMCs, reduced MMP expression, and improved cellular contractility. In addition, DKK3 KO reversed Ang II-induced suppression of the TGF-β signaling pathway, increased TGFβ3 expression, and promoted the phosphorylation of Smad2/3 downstream of the receptor.
Smad2/3 are transcription factors that when phosphorylated enter the nucleus and activate TGF-β-specific gene expression. Further studies revealed that DKK3 modulates the TGF-β signaling pathway through the transcription factor ATF6. ATF6 inhibition increased TGFβ3 levels and VSMC contractile markers, while treatment with AA147 (an ATF6 agonist) counteracted the effects of DKK3 deficiency and promoted the change in VSMC phenotype. This study demonstrates that DKK3 promotes aneurysm progression through the ATF6-mediated TGFβ3 signaling pathway, driving a shift in smooth cell phenotype toward a synthetic state, increasing MMP production, and accelerating elastin degradation.
These findings identify DKK3 as a potential therapeutic target for maintaining arterial wall homeostasis in abdominal aortic aneurysms.
- A cura del Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.
Pubblicazioni scientifiche
Cao X, Jia J et al. Research. 2025 Sep 11; 8:0873.
Ma B et al. J Mol Cell Cardiol. 2025 May; 202:35-49.
Cao G et al. Cell Commun Signal. 2022; 20(1):180.
Lu H et al. J Am Heart Assoc. 2021; 10(24):e023601.
