Complex role of thrombospondin-1 in aortic aneurysm

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 modulated.3 This is well illustrated by the findings of Zhou et al, who found no effect on aneurysm rupture in the AngII model of deficiency in TSP-1 in VSMCs or endothelial cells. In contrast, Myeloid-specific deficiency of TSP-1 promoted aortic aneurysm rupture in the AngII model. Furthermore, endothelial-specific TSP-1 deficiency reduced aortic diameter only in the calcium chloride model. It has long been believed that the mechanisms involved in initial development of aortic aneurysm are distinct from those involved in the later stages of progression and rupture.1 For example, the clinical risk factors for aortic aneurysm rupture and growth are different.1 Deficiency of TSP-1 during early as opposed to later stages of aortic aneurysm development may have very different effects. Some of the past findings suggest that TSP-1 may have a pro-aneurysmal effect in the initial stages of development.7–9 However, in more advanced aneurysms a number of studies have found TSP-1 appears to inhibit aneurysm growth and rupture.5,6,10 Indeed, several variables can shift the balance between TSP1’s pro-inflammatory and monocyte-recruiting actions and its role in promoting TGFβ-mediated matrix repair, potentially explaining the apparently conflicting outcomes. Overall, these past findings are not necessarily contradictory but may be complementary, through suggesting that TSP-1 is a critical multi-faceted protein during aortic aneurysm development and progression. However, the overall role of TSP-1 in relation to human aortic aneurysm remains unclear and may warrant further study. Research by Jonathan Golledge is supported by grants from National Health and Medical Research Council (GNT2041176/GNT2026319/GNT1180736), Medical Research Future Fund (MRF2032898/MRF2022807/MRF2015979/MRF2015817/MRF2015999), Queensland Government (Senior Clinical Research Fellowship), Heart Foundation, and Townsville Hospital and Health Services. Research by Phillip Owens is supported by National Institutes of Health grants R01-HL147171-04 (APOIII) and R01 HL179626-01 (APOIII). The authors are supported by a number of research grants as outlined in the funding statement.

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