The aorta in Marfan syndrome - from molecular mechanisms to mechanobiological dysfunction.

摘要

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that affects cardiovascular, musculoskeletal, and ocular tissues, with premature death often resulting from dissection of the thoracic aorta. MFS results from pathogenic variants in FBN1, which encodes fibrillin-1, a glycoprotein that promotes elastic fiber organization and stability and contributes to smooth muscle cell mechano-sensing of extracellular matrix. It has been 35 years since the discovery that FBN1 variants cause MFS, yet understanding links between a variant and thoracic aortic disease remains incomplete and definitive treatments remain wanting. We review advances in understanding disease progression in the aorta in MFS from perspectives of genetics, histology, mechanobiology, and biomechanics, with a focus on mouse models that include further genetic modifications to assess factors contributing to disease progression as well as effects of pharmacological treatments. This monogenic disease results in hundreds of differentially expressed genes in the aorta, many cell specific, that should be delineated as protective compensations, pathologic consequences, or neutral changes, and therapies should promote beneficial compensations and prevent detrimental consequences. Given the complexity of aortic disease in MFS, data-informed and data-driven computational models promise to help integrate multimodal data and increase understanding of molecular and cellular changes that drive disease progression, with a goal of improved therapies that prevent disease progression.