© 2000 American Heart Association, Inc.
Cellular Biology |
Laminar Shear Stress Inhibits Vascular Endothelial Cell Proliferation by Inducing Cyclin-Dependent Kinase Inhibitor p21Sdi1/Cip1/Waf1
From the Department of Pathology (S.A., M.M., Y.Y.), School of Medicine, Yamanashi Medical University, Nakakoma, Yamanashi, Japan, and the Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Correspondence to Masako Mitsumata MD, PhD, Department of Pathology, School of Medicine, Nihon University, 30-1 Kamicho, Oyaguchi, Itabashi, Tokyo 173-8610, Japan.
Abstract—Alterations in the functions of vascular endothelial cells (ECs) induced by fluid shear stress may play a pivotal role in both the development and prevention of vascular diseases. We found that DNA synthesis of bovine aortic and human umbilical vein ECs, determined by [3H]thymidine incorporation, was inhibited by steady laminar shear stress (5 and 30 dyne/cm2). This growth inhibition due to shear stress was associated with suppression of cell transition from the G1 to S phase of the cell cycle. Therefore, we studied G1-phase events to find the molecules responsible for this cell cycle arrest. Shear stress inhibited the phosphorylation of a retinoblastoma protein (pRb) and the activity of cyclin-dependent kinase (cdk) 2 and cdk4, which phosphorylate pRb. The level of cdk inhibitor p21Sdi1/Cip1/Waf1 protein, but not that of p27Kip1, increased as a result of shear stress, and the amount of p21 protein associated with cdk2 also increased, although the protein level of cdk2 was unchanged. Shear stress markedly elevated the mRNA level of p21, and this elevation in mRNA faded after the release of cells from shear stress, concomitant with a recovery of DNA synthesis. These results suggest that steady laminar shear stress induces cell cycle arrest by upregulating p21. Derangement of the steady laminar flow may release cells from this inhibition and induce cell proliferation, which, in turn, may cause atherosclerosis through the induction of EC stability disruption.
Key Words: shear stress • cell cycle arrest • p21Sdi1/Cip1/Waf1 • cyclin-dependent kinases • vascular endothelial cell
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