title: Thrombospondin-1 deficiency accelerates atherosclerotic plaque maturation in ApoE-/- mice.
abstract: Thrombospondin (TSP)1 is implicated in various inflammatory processes, but its role in atherosclerotic plaque formation and progression is unclear. Therefore, the development of atherosclerosis was compared in ApoE(-/-) and Tsp1(-/-)ApoE(-/-) mice kept on a normocholesterolemic diet. At 6 months, morphometric analysis of the aortic root of both mouse genotypes showed comparable lesion areas. Even when plaque burden increased approximately 5-fold in ApoE(-/-) and 10-fold in Tsp1(-/-)ApoE(-/-) mice, during the subsequent 3 months, total plaque areas were comparable at 9 months. In contrast, plaque composition differed substantially between genotypes: smooth muscle cell areas, mostly located in the fibrous cap of ApoE(-/-) plaques, both at 6 and 9 months, were 3-fold smaller in Tsp1(-/-)ApoE(-/-) plaques, which, in addition, were also more fibrotic. Moreover, inflammation by macrophages was twice as high in Tsp1(-/-)ApoE(-/-) plaques. This correlated with a 30-fold elevated incidence of elastic lamina degradation, with matrix metalloproteinase-9 accumulation, underneath plaques and manifestation of ectasia, exclusively in Tsp1(-/-)ApoE(-/-) mice. At 9 months, the necrotic core was 1.4-fold larger and 4-fold higher numbers of undigested disintegrated apoptotic cells were found in Tsp1(-/-)ApoE(-/-) plaques. Phagocytosis of platelets by cultured Tsp1(-/-) macrophages revealed the instrumental role of TSP1 in phagocytosis, corroborating the defective intraplaque phagocytosis of apoptotic cells. Hence, the altered smooth muscle cell phenotype in Tsp1(-/-)ApoE(-/-) mice has limited quantitative impact on atherosclerosis, but defective TSP1-mediated phagocytosis enhanced plaque necrotic core formation, accelerating inflammation and macrophage-induced elastin degradation by metalloproteinases, speeding up plaque maturation and vessel wall degeneration.
authors.affiliation: Center for Molecular and Vascular Biology, Department of Cardiovascular Diseases, University of Leuven, Belgium.
authors.forename: Rute
authors.initials: R
authors.lastname: Moura
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Petra
authors.initials: P
authors.lastname: Vandervoort
authors.forename: Soetkin
authors.initials: S
authors.lastname: Van Kerckhoven
authors.forename: Paul
authors.initials: P
authors.lastname: Holvoet
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000235:genetics; D019700:Thrombospondin 1 / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D019700:Thrombospondin 1; D004549:Elastin