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Cellular and molecular mechanisms of thoracic aortic aneurysms

Nature Reviews Cardiology volume 6, pages 771–786 (2009)Cite this article

Abstract

Thoracic aortic aneurysms (TAA) increase the risk of aortic dissection or rupture and represent an important source of morbidity and mortality. Inherited forms of the disease, including Marfan syndrome, have been recognized for a long time but were considered degenerative diseases characterized by cystic medial necrosis of the aortic wall. Improved definition of the structure and function of the normal aortic wall, coupled with the discovery of genetic mutations in key regulatory molecules, have contributed to a more detailed understanding of the pathophysiology of syndromic, familial and sporadic TAAs. We here review the cellular and molecular mechanisms involved in TAA formation and outline areas for future research.

Key Points

  • Developmental variations between the thoracic and abdominal aorta result in differences in cellular responses to similar biological stimuli

  • In addition to their structural role, the cells and proteins in the aortic wall have important regulatory functions that maintain homeostasis

  • Dysfunction of one or more components of the cytoskeleton–receptor–extracellular matrix complex can lead to structural and functional dysregulation of aortic wall properties

  • The transforming growth factor β1 pathway is important in matrix regulation in health and disease, and increased activity is a key component of various forms of thoracic aortic aneurysms (TAAs)

  • TAAs can be syndromic, familial nonsyndromic or sporadic, and are characterized by apoptosis and disarray of vascular smooth muscle cells, fragmentation of elastin, inflammatory infiltration, and upregulation of matrix metalloproteinases

  • Therapeutic strategies that target specific molecular pathways have shown promising results in mitigating TAA progression, and further understanding of the pathogenic mechanisms offers great potential for developing additional therapies

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Figure 1: The lamellar unit.
Figure 2: The cytoskeleton–receptor–ECM complex.
Figure 3: Illustration of the roles of collagen fibers in the ECM.
Figure 4: The structural and functional effects of normal and mutant fibrillin 1 in the regulation of aortic wall homeostasis.
Figure 5: Developmental origin of cells populating the ascending aorta.
Figure 6: The role of TGF-β1 in TAA formation.
Figure 7: The 'outside-in' theory showing the role of the 5-LO pathway in the formation of aortic aneurysms.
Figure 8: Typical immunohistochemical findings in an explanted aortic wall of a patient who underwent surgery for a nonfamilial TAA, compared with a normal aortic wall obtained from a transplant recipient with a normal aorta.
Figure 9: Computational modeling of structural and fluid mechanics in the aortic wall of a patient with aortic root dilatation.

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Acknowledgements

Dr. El-Hamamsy is supported by a fellowship grant from the Canadian Institute for Health Research (CIHR) and by the Magdi Yacoub Institute. The authors would like to acknowledge Dr. Padmini Sarathchandra for the electron micrograph and immunohistochemical staining, and Dr. Ryo Torii for for his help with functional imaging of aortic biomechanics.

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  1. Harefield Heart Science Centre, The Magdi Yacoub Institute, Imperial College London, UK

    Ismail El-Hamamsy & Magdi H. Yacoub

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Correspondence to Magdi H. Yacoub.

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El-Hamamsy, I., Yacoub, M. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat Rev Cardiol 6, 771–786 (2009). https://doi.org/10.1038/nrcardio.2009.191

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