Published online before print September 25, 2008, doi: 10.1161/CIRCRESAHA.108.185645
© 2008 American Heart Association, Inc.
Molecular Medicine |
Thrombospondin-1 Deficiency Accelerates Atherosclerotic Plaque Maturation in ApoE–/– Mice
From the Center for Molecular and Vascular Biology (R.M., P.V., S.V.k., M.F.H.); Center for Transgene Technology and Gene Therapy (M.T.); and Atherosclerosis and Metabolism Unit (P.H.), Department of Cardiovascular Diseases, University of Leuven, Belgium.
Correspondence to Marc Hoylaerts, PhD, Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail Marc.Hoylaerts{at}med.kuleuven.be
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 
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.
Key Words: atherosclerosis • matricellular proteins • transgenic mice • vascular inflammation
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Circ. Res. 2008 103: 1053-1055.
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