{"doi":"10.1093/cvr/cvaf274","title":"Complex role of thrombospondin-1 in aortic aneurysm","abstract":"This editorial refers to ‘Cell-dependent contributions of thrombospondin-1 to the rupture of abdominal aortic aneurysm in mice’, by T. Zhou et al., https://doi.org/10.1093/cvr/cvaf243. Aortic aneurysm, characterized by permanent dilation or expansion and weakening of the aortic wall, is an important causes of sudden death due to aortic rupture, which mainly affects older adults or younger individuals within inherited genetic mutations, including those in the transforming growth factor-β (TGFβ) pathway.1,2 Aortic aneurysm is of particular research interest because currently there are no established medical therapies to limit aneurysm progression or rupture and thus identifying drug therapy targets is an urgent focus.1,2 Thrombospondin-1 (TSP-1) is an important extracellular matrix protein that has been linked with an array of functions beyond maintaining tissue integrity, including activating TGFβ.3 TSP-1 has multiple domains with the ability to interact with a range of cell types implicated in aortic remodelling, including monocyte-macrophages, endothelial, and vascular smooth muscle cells (VSMC).3 Plasma and aortic concentrations of TSP-1 have been reported to be higher in patients with aortic dissection than controls.4 Amongst patients with small abdominal aortic aneurysms serum TSP-1 concentrations have been negatively correlated with aneurysm growth during follow-up.5 Thus, TSP-1 might be an important target for a drug therapy for aortic aneurysm. In the current issue of Cardiovascular Research, Zhou et al. investigated the effect of global, and endothelial, VSMC, and myeloid-specific deficiency of TSP-1 on aortic aneurysm formation and rupture in hypercholesterolemic mice.6 This research is particularly pertinent as past findings of the role of TSP-1 in aortic aneurysm have been conflicting (Table 1).5–10 Initial work by Liu et al. suggested that global deficiency in TSP-1 reduced aortic expansion in multiple mouse models of aortic aneurysm, including those induced by subcutaneous angiotensin II (AngII) infusion, intra-luminal aortic elastase perfusion or peri-adventitial aortic calcium phosphate administration.8 In contrast, research by Krishna et al. using the AngII mouse model found that global deficiency in TSP-1 promoted aortic expansion.5 Furthermore, a peptide which antagonized the ability of TSP-1 to activate TGFβ, promoted faster growth of established AngII-induced aortic aneurysms in hypercholesteremic mice.10 These conflicting findings stimulated a number of cell-specific studies investigating TSP-1. Yang et al. reported that myeloid-specific TSP-1 deficiency attenuated calcium chloride induced aortic expansion.9 In contrast, the current study by Zhou et al, reports that myeloid, but not VSMC or endothelial-specific, TSP-1 deficiency promotes aortic rupture in response to AngII infusion in mice. However, only endothelial-specific TSP-1 deficiency attenuated calcium chloride induced aortic diameter expansion.6 Findings of studies investigating the effect of thrombospondin-1 deficiency on aortic aneurysm development and rupture in mice Fbln4SMKO, vascular smooth muscle specific deletion of fibulin-4; VSMC, vascular smooth muscle cell; CaCl2, calcium chloride; CaPO4, calcium phosphate; AngII, angiotensin II; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix metalloproteinase; TGFβ, transforming growth factor beta; TSP1, thrombospondin-1 aMice receiving adenoviral transfer of pro-protein convertase subtilisin/kexin 9 gain of function mutation; ECM, extracellular matrix; AA, aortic aneurysm. bApolipoprotein E deficient. How are we best to make sense of these conflicting past findings? It appears likely that given the ability of TSP-1 to interact with a large range of cell types and receptors how changes in its expression influence aneurysm pathogenesis will depend on the experimental design, including stage of disease studied, mouse model used, endpoint selected, and cell type in which TSP-1 is modulat","journal":"Cardiovascular Research","year":2025,"id":587859,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1504066,"name":"A Phillip Owens","orcid":null,"position":1,"is_corresponding":false},{"id":657433,"name":"Jonathan Golledge","orcid":"0000-0002-5779-8848","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-19T02:59:39.958043Z","pmid":"41689431","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}