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The P387 Thrombospondin-4 Variant Promotes Accumulation of Macrophages in Atherosclerotic Lesions

Aims Thrombopspondin-4 (TSP4) is a pro-angiogenic protein that has been implicated in tissue remodeling and local vascular inflammation. TSP4 and, in particular, its SNP variant, P387 TSP4, have been associated with cardiovascular disease. Macrophages are central to initiation and resolution of inflammation and development of atherosclerotic lesions, but the effects of the P387 TSP4 on macrophages remain essentially unknown. We examined the effects of the P387 TSP4 variant on macrophages in cell culture and in vivo in a murine model of atherosclerosis. Further, the levels and distributions of the twoTSP4 variants were assessed in human atherosclerotic arteries. Methods and Results In ApoE−/−/P387-TSP4 knock-in mice, atherosclerotic lesions accumulated more macrophages than lesions bearing A387 TSP4. The levels of inflammatory markers were increased in lesions of ApoE−/−/P387-TSP4 knock-in mice compared to ApoE−/− mice. Lesions in human arteries from individuals carrying the P387 variant had higher levels of TSP4 and higher macrophage accumulation. P387 TSP4 was more active in supporting adhesion of cultured human and mouse macrophages in experiments using recombinant TSP4 variants and in cells derived from P387-TSP4 knock-in mice. Conclusions TSP4 supports the adhesion of macrophages and their accumulation in atherosclerotic lesions. P387 TSP4 is more active in supporting these pro-inflammatory events in the vascular wall, which may contribute to the increased association of P387 TSP4 with cardiovascular disease. Abbreviations BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; ECM, extracellular matrix; Thbs4−/−, thrombospondin-4 gene knock-out; WT, wild type; P387-TSP4 KI, P387 TSP4 knock-in mice; OCT, Optimum Cutting Temperature; vWF, von Willebrand factor; α-SMA, alpha-smooth muscle actin; Egr2, Early Growth Response 2; PBS, Phosphate Buffer saline; DMEM, Dulbecco’s Modified Eagle Medium.