Cilengitide limits the progression of both syndromic and sporadic thoracic aortic aneurysms by targeting alpha V integrins

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