GSDMD Deficiency Attenuates the Development of Ascending Aortic Dissections in a Novel Mouse Model.

Abstract

Background: Mechanisms driving the development of type A aortic dissection (TAD) are currently poorly understood, and animal models of spontaneous TAD are limited. In the present study, we developed a novel mouse TAD model and evaluated the role of GSDMD (gasdermin D) in TAD development.

Methods: TADs were created by treating the ascending aorta of adult C57BL/6J mice with Act E (active elastase) and β-aminopropionitrile. The temporal progress of the TAD pathology was rigorously characterized by histological evaluation and scanning electron microscopy, while potential mechanisms were explored using bulk RNA sequencing of specimens collected at multiple time points. With this novel TAD model, we conducted additional experiments to investigate the impact of GSDMD deficiency on TAD formation.

Results: Ascending aortas challenged with Act E and β-aminopropionitrile developed pathology featuring the early onset of intimomedial tears (complete penetration) and intramural hematomas, followed by progressive medial loss and aortic dilation. Ingenuity pathway analysis and functional annotation of differentially expressed genes suggested that a unique inflammatory microenvironment, rather than general inflammation, promotes the onset of TADs by specifically recruiting neutrophils to the aortic wall. At later stages, T cell-mediated immune injury emerged as the primary driver of pathology. Gsdmd deficiency attenuated medial loss, adventitial fibrosis, and dilation of TADs. This protective effect correlated with a reduced cell death and decreased T-cell infiltration in TADs. Notably, cleaved GSDMD was detected in human TADs but was absent in healthy aortas.

Conclusions: A novel mouse TAD model was developed, specifically targeting the ascending aorta. This model generates a unique microenvironment that activates specific immune cell subsets, driving the onset and subsequent remodeling of TADs. Consistently, Gsdmd deficiency mitigates TAD development, likely by modulating cell death and T-cell responses. This model provides a valuable tool for studying immune injury mechanisms in TAD pathogenesis.