Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections

Abstract

Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM-VSMC network.

Keywords: Aortic dissection; Biomarkers; Extracellular matrix; Mechanobiology; Thoracic aortic aneurysm; Vascular smooth muscle cells.

Fig. 1

Central illustration: Development of Precision Medicine in Thoracic Aortic Diseases gives a summary of the current clinical patient screening management based on diameter threshold (including the risk of aneurysm and rupture) and the proposed screening management with the use of clinical biomarkers as an add-in to imaging modalities to prevent invasive surgical repair and high-risk of mortality

Fig. 2

Schematic overview of major clinical risk factors in ATAA. Besides genetic syndromes, connective tissue disease, and bicuspid aortic valve morphology, these include hypertension, smoking, male sex, age, and COPD

Fig. 3

Regional heterogeneity and embryological diversity within human aorta: LM lateral mesoderm (green, located in aortic root), NC neural crest (pink, located in ascending/arch), PM paraxial mesoderm (red, located in descending aorta)

Fig. 4

An overview of suggested intra- and intercellular mechanosensitive pathways involved in vascular homeostasis (black arrows) and pathologic condition in ATAA (red arrows). In impaired vascular homeostasis, intracellular pathways leading to nuclear translocation of Hippo pathway effector YAP inducing proliferation. Downregulation of Notch1 and DLL1/4 proteins can have significant effects on cellular function and may impact various physiologic processes. When Notch1 and DLL1/4 proteins are downregulated, it can lead to reduced activation of Notch Intracellular Domain (NICD). In this scenario, the transcriptional repressor Hes1 fails to activate, which is pivotal for VSMC proliferation. Therefore, dysregulation of the Notch signaling pathway could potentially contribute to pathologic processes involved in the development and progression of ATAA