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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2163.)
© 2007 American Heart Association, Inc.

Vascular Biology

Thrombospondin-1 Activates Medial Smooth Muscle Cells and Triggers Neointima Formation Upon Mouse Carotid Artery Ligation

Rute Moura; Marc Tjwa; Petra Vandervoort; Katrien Cludts; Marc F. Hoylaerts

From the Center for Molecular and Vascular Biology (R.M., P.V., K.C., M.F.H.) and the Center for Transgene Technology and Gene Therapy (M.T.), 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

Objective— Thrombospondin-1 (TSP1) is described as a positive regulator of vascular smooth muscle growth in cell culture. However, insight into the in vivo effects of TSP1 on smooth muscle cell (SMC) function is lacking.

Methods and Results— We analyzed wild-type (WT) and TSP1-deficient (Tsp1^–/–) mice in a carotid artery ligation model, in which neointimal lesions form without overt mechanical damage to the endothelium. On ligation, the expression of TSP1 increased strongly in the matrix of neointima and adventitia. In the early phase after ligation (day 3 to 7), activation, proliferation, and migration of medial SMCs were delayed and impaired in Tsp1^–/– mice, in parallel with defective upregulation of metalloproteinase (MMP)-2 activity. As a result, Tsp1^–/– arteries developed smaller neointimal lesions, a thicker media but comparably attenuated patency as in WT arteries, 28 days after ligation. Furthermore, medial and neointimal SMCs in Tsp1^–/– mice produced more collagen, more osteopontin, and displayed weaker smooth muscle actin staining than WT SMCs, indicative of a modified SMC phenotype in Tsp1^–/– mice.

Conclusions— Arterial SMC activation in the absence of TSP1 is delayed and dysregulated, reducing neointima formation, on mild vascular injury.

We analyzed WT and Tsp1^–/– mice in a neointima model without endothelial denudation. Early proliferation and migration of medial SMCs were delayed and impaired. As a result, Tsp1^–/– arteries developed smaller neointimas, thicker media, but comparably attenuated patency as in WT arteries. Tsp1^–/– SMCs had a modified profibrotic phenotype.

Key Words: carotid artery • matricellular proteins • neointima • smooth muscle cells