Abstract 4360006: Endothelial SMARCD2 Exacerbates Aortic Aneurysm and Dissection Through Inflammatory Signaling

Background: Aortic aneurysm and dissection (AAD) remain the major causes of cardiovascular mortality, and there are currently no effective pharmacological treatments. The chromatin remodeler SMARCD family members have been recently implicated in vascular pathology, but the role of SMARCD2 in endothelial cells (ECs) during AAD remains unknown. Methods: To investigate the EC-specific function of SMARCD2, we generated Smarcd2 EC-specific knockout ( Smarcd2 ECKO ) mice by crossing Smarcd2 fl/fl mice with VE-Cre mice. AAD was induced using the β-aminopropionitrile (BAPN) and angiotensin II (AngII) in 10–12-week-old male mice. RNA sequencing and inflammatory signaling were assessed in HUVEC with SMARCD2 knockdown following IL-1β stimulation. To explore the underlying mechanisms, we engineered a SMARCD2-TurboID fusion protein for proximity-dependent biotinylation and mass spectrometry analysis to identify the SMARCD2-interacting partners. Results: Smarcd2 ECKO mice exhibited improved survival compared to Smarcd2 fl/fl controls. Surviving Smarcd2 ECKO mice had reduced aortic diameters (1.82 ± 0.67 vs. 1.15 ± 0.11 mm, n = 7, p = 0.024), indicating protection against AAD development. In vitro , SMARCD2 knockdown in HUVEC attenuated IL-1β-induced inflammatory gene expression. Activation levels were calculated as fold changes relative to control siRNA–treated cells without IL-1β stimulation. SMARCD2 knockdown significantly reduced the IL-1β-induced upregulation of ICAM1 (448.5 ± 42.9 vs. 156.5 ± 72.6, p < 0.01), SELE (151.9 ± 14.0 vs. 112.8 ± 4.9, p = 0.01), IL1A (9.4 ± 1.3 vs. 7.0 ± 0.7, p = 0.04), CCL2 (244.5 ± 21.0 vs. 164.0 ± 37.6, p = 0.03), IL6 (1717.0 ± 44.0 vs. 1113.0 ± 82.5, p < 0.01), CXCL3 (3451.0 ± 298.0 vs. 2346.0 ± 319.8, p = 0.01). Proteomic analysis using SMARCD2-TurboID, followed by Western blot validation, revealed significant enrichment of p65, c-Jun, and c-Fos, compared to the TurboID-NLS control. These results suggest that SMARCD2 cooperates with NF-κB and AP-1 complexes to promote pro-inflammatory signaling in endothelial cells. Conclusion: Endothelial-specific deletion of Smarcd2 protects against AAD development by dampening inflammatory responses. Mechanistically, SMARCD2 interacts with key transcriptional regulators of inflammation, including NF-κB and AP-1, positioning it as a potential therapeutic target in aortic disease.