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

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.

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-1^VSMC)-were carried out. Thrombospondin (THBS4, TSP4) was knocked down in vivo by lentiviral RNA interference.

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-1^VSMC 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.

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.