Thrombospondin-1 activates medial smooth muscle cells and triggers neointima formation upon mouse carotid artery ligation.
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.


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.
Moura
Rute
R
Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Tjwa
Marc
M
Vandervoort
Petra
P
Cludts
Katrien
K
Hoylaerts
Marc F
MF
D000199:Actins / Q000378:metabolism; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D005838:Genotype; D006965:Hyperplasia; D008026:Ligation; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D053495:Osteopontin / Q000378:metabolism; D010641:Phenotype; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology*; D014654:Vascular Patency
D000199:Actins; C506896:Spp1 protein, mouse; D019700:Thrombospondin 1; D053495:Osteopontin; D003094:Collagen; D020778:Matrix Metalloproteinase 2