Thrombospondin-4 regulates vascular inflammation and atherogenesis

Rationale—Thrombospondin-4 (TSP-4) is an extracellular protein that has been linked to several cardiovascular pathologies. However, a role for TSP-4 in vascular wall biology remains unknown. Objective—We have examined the effects of TSP-4 gene (Thbs4) knockout on the development of atherosclerotic lesions in ApoE−/ − mice. Methods and Results—Deficiency in TSP-4 reduced atherosclerotic lesions: at 20 weeks of age, the size of the aortic root lesions in Thbs4−/−/ApoE−/ − mice was decreased by 48 % in females and by 39 % in males on chow diets; in mice on Western diets, lesions in the descending aorta were reduced by 30 % in females and 33 % in males. In ApoE−/ − mice, TSP-4 was abundant in vessel areas prone to lesion development and in the matrix of the lesions themselves. TSP-4 deficiency reduced the number of macrophages in lesions in all groups by ≥ 2 fold. In addition, TSP-4 deficiency reduced endothelial cell activation (expression of surface adhesion molecules) and other markers of inflammation in the vascular wall (decreased production of MCP-1 and activation of p38). In vitro, both the adhesion and migration of wild-type macrophages increased in the presence of purified recombinant TSP-4 in a dose-dependent manner (up to 7 and 4.7 fold