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Am J Physiol Heart Circ Physiol 277: H1100-H1106, 1999;
0363-6135/99 $5.00
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Vol. 277, Issue 3, H1100-H1106, September 1999

Vascular smooth muscle cell growth arrest on blockade of thrombospondin-1 requires p21Cip1/WAF1

Donghui Chen1, Kun Guo1, Jihong Yang1, William A. Frazier3, Jeffrey M. Isner1, and Vicente Andrés1,2

1 Department of Medicine (Cardiology), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135; 2 Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, 46010 Valencia, Spain; and 3 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110

Abnormal proliferation of vascular smooth muscle cells (VSMCs) is thought to play an important role in the pathogenesis of atherosclerosis and restenosis. Previous studies have implicated the extracellular matrix protein thrombospondin-1 (TSP1) in mitogen-dependent proliferation of VSMCs. In this study, we investigated the molecular mechanisms involved in TSP1-mediated regulation of VSMC growth. Neutralizing A4.1 anti-TSP1 antibody inhibited the activity of the G1/S cyclin-dependent kinase 2 (cdk2) and blocked the induction of S-phase entry, which normally occurs in serum-stimulated VSMCs. This growth-inhibitory effect was associated with a marked induction of p21Cip1/WAF1 (p21) expression in A4.1-treated VSMCs. Moreover, addition of A4.1 antibody to VSMCs markedly increased the level of p21 bound to cdk2. Thus growth arrest on antibody blockade of TSP1 may be mediated by the cdk inhibitory protein p21. Consistent with this notion, anti-TSP1 antibody inhibited [3H]-thymidine incorporation in wild-type but not in p21-deficient mouse embryonic fibroblasts (MEFs). Together, these data suggest that p21 plays an important role in TSP1-mediated control of cellular proliferation.

cell cycle control; p21Cip1/WAF1; thrombospondin; extracellular matrix


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