Thrombospondin-4 is upregulated in abdominal aortic aneurysm: A vasoprotective response with potential therapeutic relevance

Background and purpose: Extracellular matrix (ECM) remodelling is critical in abdominal aortic aneurysm (AAA), a life-threatening condition lacking effective pharmacotherapy. However, key ECM components regulating vascular integrity and remodelling remain poorly understood. Experimental Approach: Transcriptome profiling and studies in human AAA and in aneurysms from two models susceptible to angiotensin II (Ang II)-induced AAA—apolipoprotein E knockout mice (ApoE−/−) and transgenic mice overexpressing the nuclear receptor NOR-1 in the vasculature (TgNOR-1VSMC)—were carried out. Thrombospondin (THBS4, TSP4) was knocked down in vivo by lentiviral RNA interference. Key results: Transcriptome profiling highlighted the relevance of the ECM-mediated pathway and the upregulation of THBS4 in human AAA. In a large cohort of patients and donors and in Ang II-infused ApoE−/− and TgNOR-1VSMC mice, we confirmed the significant increase of aortic THBS4 mRNA and TSP4 protein levels in AAA and found that THBS4 was early upregulated in pre-aneurysmal lesions. THBS4 was mainly detected in the adventitia of mouse aorta and in cell cultures from fibroblasts or IFNγ-stimulated macrophages. Accordingly, in AAA, TSP4 immunostaining was predominant in adventitial fibroblasts and macrophages. Thbs4 blockade shifted macrophages and fibroblasts towards a more pro-inflammatory phenotype, whereas, in Ang II-challenged ApoE−/− mice, aortic Thbs4 knockdown by lentiviral transduction accelerated disease progression, increasing aortic diameter and aggravating both vascular inflammation and remodelling. Conclusions and implications: We uncover the early and sustained induction of TSP4 in AAA and its protective role in limiting vascular inflammation and destructive remodelling. Modulation of TSP4-dependent pathways may represent a novel avenue to improve vascular stability in AAA.