ELABELA Protects Against Thoracic Aortic Dissection by Maintaining Vascular Smooth Muscle Cells Homeostasis and Regulating NETosis

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Disruption of vascular smooth muscle cell (VSMC) homeostasis plays a vital role in triggering TAD. ELA (ELABELA) is a novel endogenous ligand for APJ (angiotensin receptor AT1-related receptor protein). However, the effects of ELA on TAD formation and development remain elusive. METHODS: Four-week-old C57BL/6J male mice were treated with β-aminopropionitrile monofumarate or β-aminopropionitrile monofumarate combined with Ang II (angiotensin II) to induce TAD models, and the aortic rupture occurred mainly in the descending thoracic region. ELA or saline was infused via osmotic minipumps into mice for 4 weeks. Transcriptomic studies and VSMC-derived conditioned medium were used to investigate the downstream molecular mechanisms of ELA. RESULTS: ELA infusion mitigated TAD development and prevented aortic media degradation in mice, which was reversed by APJ antagonist ML221. Exogenous ELA prevented the disruption of VSMC homeostasis under PDGF (platelet-derived growth factor) stimulation in VSMCs. Based on transcriptomic studies, we showed that ELA significantly inhibits NLRP3 (NLR family pyrin domain-containing 3)/IL (interleukin)-1β pathway activation and modulates NET (neutrophil extracellular trap) formation in vivo and in vitro. In human neutrophils, ELA significantly inhibited NETs' formation, which is prevented by reactive oxidative species supplementation. Using VSMC-derived conditioned medium, we showed that NLRP3/IL-1β-related NETs' formation connects cellular signaling from VSMCs to neutrophils, leading to disruption of VSMC homeostasis. Notably, ELA was downregulated in both plasma and aortic tissues of human TAD, and lower plasma ELA levels were associated with an increased risk of TAD. CONCLUSIONS: We provide evidence that ELA prevents TAD progression and aortic medial degeneration, primarily by maintaining VSMC homeostasis, which may be linked to the inhibition of NETosis in neutrophils and NLRP3/IL-1β-related cellular signaling between VSMCs and neutrophils. ELA shows promise as a target for pharmacological therapy and diagnostic TAD management.