NF-κB-Mediated Upregulation of Tissue Factor Contributes to the Procoagulant Phenotype of Smooth Muscle Cells from Abdominal Aorta Aneurysm in Human

Abstract

Background

Aneurysms of the thoracic (TAA) and abdominal aorta (AAA) have different pathophysiological mechanisms. AAA has an intraluminal thrombus, while TAA does not. This suggests a prothrombotic phenotype in AAA, probably at the level of vascular smooth muscle cells (SMCs) known to express tissue factor (TF).

Objectives

To explore the TF-dependent thrombin generation in SMCs in AAA compared with TAA and healthy aorta (HA) and the underlying mechanisms contributing to a procoagulant phenotype.

Methods

Human HA, AAA, or TAA tissues and corresponding SMC primary cultures were used to analyze SMC-supported thrombin generation and TF expression.

Results

In the absence of added TF, thrombin generation was increased at the surface of SMCs from AAA compared with TAA and HA, indicating a cellular procoagulant phenotype, which is transmitted through mitosis. Phosphatidylserine exposure was increased at the surface of SMCs from AAA. As expected, reactive oxygen species generation and the proinflammatory cytokine TNF-α were increased in SMCs from AAA. Overexpression of protease-activated receptor 2 and nuclear translocation of NF-κB p65 in SMCs and tissue from AAA triggered increased TF gene expression. Higher active basal TF expression was also observed in SMCs from AAA, which was inhibited by BAY 11–7082 (pharmacological inhibitor of IκK) and GB83 (pharmacological inhibitor of PAR-2).

Conclusion

We demonstrated a PAR-2-mediated activation of the canonical NF-κB pathway, which triggers TF transcription in AAA. This procoagulant profile is transmitted from tissue to primary SMC cultures and through numerous passages, which can maintain thrombus formation.

Keywords

aneurysm - smooth muscle cell - tissue factor - thrombin

Authors' Contribution

M.D., V.O., C.L., J.L., H.L., and V.R. performed experiments. P.L., J.B.M., V.R., and S.M. designed and supervised the study. V.R., C.V.D., P.L., and J.B.M. wrote the manuscript. All authors contributed to the editing of the manuscript.

^* These authors contributed equally to this work and are joint last authors.

Publikationsverlauf

Eingereicht: 31. März 2025

Angenommen: 23. Juli 2025

Accepted Manuscript online:
25. Juli 2025

Artikel online veröffentlicht:
12. August 2025

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