The NOR-1/SPP1/OPN axis as a driver of abdominal aortic aneurysm

The nuclear receptor NOR-1 is a key transcription factor in vascular smooth muscle cells (VSMCs) implicated in the pathogenesis abdominal aortic aneurysm (AAA), a life-threatening disease lacking pharmacological options. Here, we aimed at identifying potential therapeutic targets regulated by NOR-1 in the onset and progression of AAA. RNA-seq analysis in dilated arteries from AngII-infused transgenic mice overexpressing NOR-1 in VSMCs (TgNOR-1^VSMC) revealed an early transcriptomic signature enriched in immune-inflammatory and tissue remodeling pathways. Biologically informed analysis identified a set of genes (Spp1, Il6, Tnfsf11, Grem1, Fcgr4, Adam8 and Mmp9), linking immune-inflammatory and vascular remodeling pathways, upregulated in TgNOR-1^VSMC dilated aortas. Re-analysis of RNA-seq datasets from human AAA aortas revealed the activation of inflammation- and extracellular matrix (ECM)-related pathways, with SPP1 and IL6 as the most upregulated genes in both clusters. In human AAA, NOR-1 expression correlated with that of SPP1 and IL6, while luciferase reporter assays and site-directed mutagenesis indicated that NOR-1 increases SPP1 transcriptional activity. Consistently, gain- and loss-of-function studies showed that NOR-1 regulates SPP1 expression. Integrative co-expression and protein-protein interaction analysis in human AAA identified SPP1 as a critical element at the cross-road between ECM remodelling and vascular inflammation. Inhibition of osteopontin (OPN, encoded by Spp1) with HY-146064 attenuated AngII-induced AAA in TgNOR-1^VSMC mice, limiting vascular remodelling, oxidative stress, and inflammation. Overall, we identify NOR-1 as an early driver of transcriptional reprogramming in AAA, establishing the NOR-1/SPP1/OPN axis as a key mediator of the cross-talk between inflammation and vascular remodelling, and a potential therapeutic target for disease intervention.