Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

Abstract

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder.

Stem Cell Based Approaches to Modulate the Matrix Milieu in Vascular Disorders

“…Thoracic aneurysms are classified as aortic root or ascending aortic aneurysms ( 60 ). The common characteristic of TAADs involves cystic medial degeneration, which manifests as degenerated elastic fibers, disorganized collagen fibers, and accumulated PGs, besides a contractile to activated phenotype switch of medial SMCs, and later apoptosis of these cells ( 60 ). In healthy vessels, vascular SMCs maintain ECM homeostasis by maintaining a perfect balance between secreted proteases (MMPs) and their inhibitors (TIMPs).…”

“…Cystic medial degeneration in absence of overt connective-tissue disorders, now referred as familial TAA syndrome, is caused mostly through defect in ACTA2 gene which encodes smooth muscle α2 actin. Mutation in ACTA2 leads to vascular SMCs with disorganized and aggregated actin filaments, and subsequently impairs their cellular adaptation to local mechanical stress in the aortic wall ( 60 ).…”

Augmentation Index in Patients with Thoracic Aortic Aneurysm: A Matched Case-Control Study

“…Additionally, chronic inflammation and changes in structural elements of the arterial wall, in vascular smooth muscle tone and endothelial dysfunction are associated with increased arterial stiffness [ 11 , 12 ]. Altered aortic wall structure, dedifferentiated smooth muscle cells, endothelial dysfunction as well as inflammation has been shown to be associated with TAA formation or progression [ 13 , 14 , 15 , 16 ]. Changes in the arterial wall are therefore associated with both the pathogenesis of TAA and arterial stiffness.…”

Aortic Aneurysm and Dissection: Heterogeneity and Molecular Mechanisms

“…Thoracic aortic aneurysms (TAA) are the second most common aortic aneurysms. Asano and colleagues [ 16 ] provided an extensive review on TAAs attributed to a relatively common genetic disease in humans: Marfan syndrome. Many patients with Marfan syndrome suffer from TAA caused by genetic changes of an extracellular protein fibrillin-1.…”

“…Mouse models with fibrillin-1 manipulations mimic the human disease. As reviewed by Asano et al, mouse models provided great mechanistic insights into TAAs of this devastating disease [ 16 ].…”