Thrombospondin-1 deficiency accelerates atherosclerotic plaque maturation in ApoE-/- mice.

Rute Moura, Marc Tjwa, Petra Vandervoort, Soetkin Van Kerckhoven, Paul Holvoet, Marc F Hoylaerts

Center for Molecular and Vascular Biology, Department of Cardiovascular Diseases, University of Leuven, Belgium.

Circulation research 2008 Nov 7

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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 phag ocytosis enhanced plaque necrotic core formation, accelerating inflammation and macrophage-induced elastin degradation by metalloproteinases, speeding up plaque maturation and vessel wall degeneration.

Citation

Rute Moura, Marc Tjwa, Petra Vandervoort, Soetkin Van Kerckhoven, Paul Holvoet, Marc F Hoylaerts. Thrombospondin-1 deficiency accelerates atherosclerotic plaque maturation in ApoE-/- mice. Circulation research. 2008 Nov 7;103(10):1181-9