Abstract 2022: AlphaV Integrins Inhibition Downregulates Pro-fibrotic Events In Human Aortic Smooth Muscle Cells And Limits Thoracic Aortic Aneurysm Progression In Marfan Mice

Abstract

Aortic dilation can often lead to lethal events, such as aortic dissection and/or vessel rupture. The aneurysms occurring in the thoracic aortic trait (TAA) may depend on comorbidities, such as hypertension, or on genetically determined conditions, such as Marfan syndrome (MFS). To date, the surgical replacement of aorta represents the most effective therapeutic approach in all TAA patients, since an etiologic pharmacological treatment is still lacking. Integrin receptors are key players in cellular mechanotransduction responses and the role of integrins containing αV subunit have been described as responsible for pro-fibrotic molecular events. Recently, it has been reported the effectiveness of a pan αV integrin inhibitor ( i.e. , GLPG0187) in limiting the TAA progression in MFS in vivo model. However, the specific αV integrin subgroup directly involved in this detrimental process is yet not known. We evaluated the effectiveness of the specific αVβ3 and αVβ5 integrin inhibitor cilengitide in downregulating pro-fibrotic in vitro events on MFS patients’ vascular smooth muscle cells (MFS-VSMC), and in limiting in vivo thoracic aortic dilation on a MFS mice model. By comparison with healthy control (HC)-VSMC, MFS-VSMC showed higher levels of αVβ3 and αVβ5 integrins as well as pro-fibrotic collagen I. When compared with GLPG0187, the cilengitide-mediated in vitro inhibition of these integrins determined a more effective downregulation of TGF-β downstream pathways (SMAD2/3 and ERK1/2) as well as a statistical tempered expression of pro-fibrotic mechanotransduction mediators, such as RhoA GTPase. The 2D-echocardiographic results on MFS mice (Fbn1 C1039G/+ ) treated with cilengitide confirmed the greater effectiveness of this drug in limiting the TAA progression, not only in comparison with vehicle but also with the broad pan αV integrin inhibitor GLPG0187. Altogether, our results improve the know-how on αV integrin involvement in MFS-TAA scenario, unveiling the specific detrimental role of αVβ3 and αVβ5 in this pathological context. The selective inhibition of these integrins exerted by cilengitide highlights the role of this compound as a potential and more targeted tool for future therapeutic approaches to limit TAA progression in MFS patients.