Abstract
Thoracic aortic aneurysm (TAA) is a complex life-threatening disease characterized by extensive extracellular matrix (ECM) fragmentation and persistent inflammation, culminating in a weakened aorta. Although evidence suggests defective canonical signaling pathways in TAA, the full spectrum of mechanisms contributing to TAA is poorly understood, therefore limiting the scope of drug-based treatment. Here, we used a sensitive RNA sequencing approach to profile the transcriptomic atlas of human TAA. Pathway analysis revealed upregulation of key matrix-degrading enzymes and inflammation coincident with the axonal guidance pathway. We uncovered their novel association with TAA and focused on the expression of Semaphorins and Netrins. Comprehensive analysis of this pathway showed that several members were differentially expressed in TAA compared to controls. Immunohistochemistry revealed that Semaphorin4D and its receptor PlexinB1, similar to Netrin-1 proteins were highly expressed in damaged areas of TAA tissues but faintly detected in the vessel wall of non-diseased sections. It should be considered that the current study is limited by its sample size and the use of internal thoracic artery as control for TAA for the sequencing dataset. Our data determines important neuronal regulators of vascular inflammatory events and suggest Netrins and Semaphorins as potential key contributors of ECM degradation in TAA.
Highlights
Thoracic aortic aneurysm (TAA) is a complex degenerative vascular disease distinguished by the progressive enlargement of the thoracic aortic vessel wall diameter, which can reach up to 1.5 times the normal aortic size [1]
We acknowledge that some of the differential expression patterns might reflect differences coupled with intrinsic properties of the aortic tissues, it is unlikely that all of the significant changes detected are unassociated to TAA since internal thoracic artery (ITA) did not present any signs of pathology
Since pathological extracellular matrix remodeling by matrix metalloproteinases (MMP) have been described to promote TAA development, [14,15] we first screened for MMP variants in our dataset
Summary
Thoracic aortic aneurysm (TAA) is a complex degenerative vascular disease distinguished by the progressive enlargement of the thoracic aortic vessel wall diameter, which can reach up to 1.5 times the normal aortic size [1]. With a three-year survival rate of 20% for patients with large dilated aneurysms, the disease is currently the 14th leading cause of death in the United States [2,3]. It is estimated that the incidence of TAA is ~5–10 in 100,000 people per year [4]. Because TAA are asymptomatic, they can go undetected over a lifetime, making the actual incidence difficult to ascertain. The majority of TAA expand silently over time and are found incidentally on imaging. Increase in size of TAA is a predictor of devastating aortic dissection and rupture and is invariably fatal without prompt surgical intervention
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