Aortopathy in Marfan syndrome: an update

Abstract

Marfan syndrome (MFS) is an inherited autosomal dominant multisystem disease caused by mutations in the FBN1 gene encoding fibrillin-1, an extracellular matrix glycoprotein widely distributed in mesenchymal-derived tissues that provide a scaffold for elastin deposition. MFS is characterized by variable clinical manifestations, including skeletal, ocular, and cardiovascular abnormalities; ascending aortic aneurysm with ensuing dissection and rupture is the main life-threatening cardiovascular manifestation of MFS. Histological aspects of MFS aortopathy include a medial degeneration from disarray and fragmentation of elastic fibers and accumulation of basophilic ground substance areas depleted of smooth muscle cells (SMCs). Transmission electron microscopy well evidences the high number of interruptions and the thick appearance of the elastic lamellae and the accumulation of abundant extracellular glycosaminoglycan-rich material, sometimes SMCs showing a prevalent synthetic phenotype. The aberrant signaling of transforming growth factor-β (TGF-β) as the consequence of the altered structure of fibrillin-1 induces activation and the overexpression of Smad-dependent profibrotic signaling pathway and ERK1/2-mediated increased synthesis of matrix metalloproteinases. In addition, MFS is accompanied by an impaired aortic contractile function and aortic endothelial-dependent relaxation, which is caused by an enhancement of the oxidative stress and increased reactive oxygen species during the progression of the disease. Many studies are currently evaluating the contribution of TGF-β-mediated biomolecular pathways to the progression of MFS aortopathy and aneurysm development, in order to discover new targets for pharmacological strategies aimed to counteract aortic dilation.

Keywords: Erk; Fibrillin-1; Marfan syndrome; Matrix metalloproteinases; Oxidative stress; Smooth muscle cells; TGF-β; Thoracic aortic aneurysm.