Thoracic aortic aneurysm is a life-threatening condition due to either genetic syndromes (e.g., Marfan syndrome) or cardiovascular risk factors (e.g., hypertension, aging and smoking), which favour the onset of sporadic thoracic aneurysms. Activation of the transforming growth factor-β pathway and dysregulation of mechanotransduction signals in vascular smooth muscle cells play a key role in the development of both syndromic and sporadic forms of thoracic aortic aneurysm. The precise molecular mechanisms underlying thoracic aortic aneurysm onset and progression are still unresolved and available therapies merely rely on surgical intervention.

Integrins containing the αV subunit are central to both transforming growth factor-β (TGF-β) and mechanotransduction signalling pathways, leading to pro-fibrotic molecular events. Here we investigate the role of αV integrins in the development of both syndromic and sporadic thoracic aortic aneurysms and the therapeutic potential of two αV integrin inhibitors (Cilengitide and GLPG0187). We observed that αV integrins are more expressed in both types of human thoracic aortic aneurysms and that integrin inhibition limits TGF-β activation and mechanotransduction-related pro-fibrotic pathways in patient-derived vascular smooth muscle cells. In vivo experiments revealed that Cilengitide is the most effective αV integrin inhibitor in limiting the dilation of the aortic bulb in murine models of both syndromic and sporadic forms of thoracic aortic aneurysms. These findings set the αV integrin inhibitor Cilengitide as a promising drug for the treatment of thoracic aortic aneurysms.

The authors have declared no competing interest.

This research was supported by the Italian Ministry of Health funds (Ricerca Finalizzata GR-2021-12371950 and RC2022-4.03 ID: 2771963), Fondazione Gigi e Pupa Ferrari ONLUS (FPF-14) and by Italian Ministry of Research (PRIN 2022, No. 2022Y849WY).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All patients signed and gave written informed consent for tissue collection for research purposes and the procedures were approved by Ethics Committee either of Centro Cardiologico Monzino IRCCS (RE3001-CCM 1462) and ASST FBF-Sacco (Prot. N. 39138/2016, Milan, Italy).

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Data of this study are available from the corresponding author upon reasonable request on ZENODO (doi: 10.5281/zenodo.15064795).