Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin-myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-beta (TGF-beta). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

Automated summary

Thoracic aortic aneurysms (TAA) are permanent dilations of the aorta that predispose patients to life-threatening aortic dissection or rupture. Pathogenic variants causing hereditary TAA compromise molecular processes essential for aortic homeostasis. These variants impair signal transduction and signaling pathways involved in the modulation of vascular smooth muscle cells (VSMCs) responses to mechanical and biochemical cues from their environment, ultimately leading to vessel degeneration and mechanical failure.