© 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
This article has been cited by other articles:
 |
|
 |
|
  E. Metaxa, H. Meng, S. R. Kaluvala, M. P. Szymanski, R. A. Paluch, and J. Kolega Nitric oxide-dependent stimulation of endothelial cell proliferation by sustained high flow Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H736 - H742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Han, Y. Miwa, H. Obikane, M. Mitsumata, F. Takahashi-Yanaga, S. Morimoto, and T. Sasaguri Aryl hydrocarbon receptor mediates laminar fluid shear stress-induced CYP1A1 activation and cell cycle arrest in vascular endothelial cells Cardiovasc Res, March 1, 2008; 77(4): 809 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Chang, M. E. O'Donnell, and A. I. Barakat Shear stress and 17{beta}-estradiol modulate cerebral microvascular endothelial Na-K-Cl cotransporter and Na/H exchanger protein levels Am J Physiol Cell Physiol, January 1, 2008; 294(1): C363 - C371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Artwohl, K. Muth, K. Kosulin, R. de Martin, T. Holzenbein, G. Rainer, A. Freudenthaler, N. Huttary, L. Schmetterer, W. K. Waldhausl, et al. R-(+)-{alpha}-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1 Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E681 - E689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Avvisato, X. Yang, S. Shah, B. Hoxter, W. Li, R. Gaynor, R. Pestell, A. Tozeren, and S. W. Byers Mechanical force modulates global gene expression and beta-catenin signaling in colon cancer cells J. Cell Sci., August 1, 2007; 120(15): 2672 - 2682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Guo, S. Chien, and J. Y.-J. Shyy Regulation of Endothelial Cell Cycle by Laminar Versus Oscillatory Flow: Distinct Modes of Interactions of AMP-Activated Protein Kinase and Akt Pathways Circ. Res., March 2, 2007; 100(4): 564 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chien Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1209 - H1224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. V. Jones, F. le Noble, and A. Eichmann What Determines Blood Vessel Structure? Genetic Prespecification vs. Hemodynamics. Physiology, December 1, 2006; 21(6): 388 - 395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zeng, Q. Xiao, A. Margariti, Z. Zhang, A. Zampetaki, S. Patel, M. C. Capogrossi, Y. Hu, and Q. Xu HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells J. Cell Biol., September 25, 2006; 174(7): 1059 - 1069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D'Arcangelo, V. Ambrosino, M. Giannuzzo, C. Gaetano, and M. C. Capogrossi Axl receptor activation mediates laminar shear stress anti-apoptotic effects in human endothelial cells Cardiovasc Res, September 1, 2006; 71(4): 754 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Miyagi, Y. Miwa, F. Takahashi-Yanaga, S. Morimoto, and T. Sasaguri Activator Protein-1 Mediates Shear Stress-Induced Prostaglandin D Synthase Gene Expression in Vascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 970 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-W. Ni, H.-J. Hsieh, Y.-J. Chao, and D. L. Wang Interleukin-6-induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow Am J Physiol Cell Physiol, September 1, 2004; 287(3): C771 - C780. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Andres Control of vascular cell proliferation and migration by cyclin-dependent kinase signalling: new perspectives and therapeutic potential Cardiovasc Res, July 1, 2004; 63(1): 11 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Aoudjit and J. Sevigny P21Waf1/Cip1 in endothelial cell survival Cardiovasc Res, March 1, 2004; 61(4): 648 - 650. [Full Text] [PDF]
|
|
|
|
|
|
S. Mattiussi, P. Turrini, L. Testolin, F. Martelli, G. Zaccagnini, A. Mangoni, L. M Barlucchi, A. Antonini, B. Illi, C. Cirielli, et al. p21Waf1/Cip1/Sdi1 mediates shear stress-dependent antiapoptotic function Cardiovasc Res, March 1, 2004; 61(4): 693 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Pi, C. Yan, and B. C. Berk Big Mitogen-Activated Protein Kinase (BMK1)/ERK5 Protects Endothelial Cells From Apoptosis Circ. Res., February 20, 2004; 94(3): 362 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M Wasserman and J. N Topper Adaptation of the endothelium to fluid flow: in vitro analyses of gene expression and in vivo implications Vascular Medicine, February 1, 2004; 9(1): 35 - 45. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Yamamoto, T. Takahashi, T. Asahara, N. Ohura, T. Sokabe, A. Kamiya, and J. Ando Proliferation, differentiation, and tube formation by endothelial progenitor cells in response to shear stress J Appl Physiol, November 1, 2003; 95(5): 2081 - 2088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Q. Liu, D. Tang, C. Tieche, and P. K. Alkema Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: mediation by gradient of cell density Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1072 - H1080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Q. Liu, C. Tieche, D. Tang, and P. Alkema Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: role of PDGF-{beta} receptor and Src Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1081 - H1090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zeng, Y. Zhang, S. Chien, X. Liu, and J. Y.-J. Shyy The Role of p53 Deacetylation in p21Waf1 Regulation by Laminar Flow J. Biol. Chem., June 27, 2003; 278(27): 24594 - 24599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Taba, M. Miyagi, Y. Miwa, H. Inoue, F. Takahashi-Yanaga, S. Morimoto, and T. Sasaguri 15-Deoxy-{Delta}12,14-prostaglandin J2 and laminar fluid shear stress stabilize c-IAP1 in vascular endothelial cells Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H38 - H46. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Y.-J. Shyy and S. Chien Role of Integrins in Endothelial Mechanosensing of Shear Stress Circ. Res., November 1, 2002; 91(9): 769 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Inoue, Y. Taba, Y. Miwa, C. Yokota, M. Miyagi, and T. Sasaguri Transcriptional and Posttranscriptional Regulation of Cyclooxygenase-2 Expression by Fluid Shear Stress in Vascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., September 1, 2002; 22(9): 1415 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Abumiya, T. Sasaguri, Y. Taba, Y. Miwa, and M. Miyagi Shear Stress Induces Expression of Vascular Endothelial Growth Factor Receptor Flk-1/KDR Through the CT-Rich Sp1 Binding Site Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 907 - 913. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Brooks, P. I. Lelkes, and G. M. Rubanyi Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow Physiol Genomics, April 10, 2002; 9(1): 27 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. De Marchis, D. Ribatti, C. Giampietri, A. Lentini, D. Faraone, M. Scoccianti, M. C. Capogrossi, and A. Facchiano Platelet-derived growth factor inhibits basic fibroblast growth factor angiogenic properties in vitro and in vivo through its alpha receptor Blood, March 15, 2002; 99(6): 2045 - 2053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. C. CHEN, Y.-S. LI, Y. ZHAO, K.-D. CHEN, S. LI, J. LAO, S. YUAN, J. Y.-J. SHYY, and S. CHIEN DNA microarray analysis of gene expression in endothelial cells in response to 24-h shear stress Physiol Genomics, October 10, 2001; 7(1): 55 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. K. Schiller, N. Kubo, W. A. Boisvert, and L. K. Curtiss Effect of {gamma}-Irradiation and Bone Marrow Transplantation on Atherosclerosis in LDL Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., October 1, 2001; 21(10): 1674 - 1680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R. White, M. Haidekker, X. Bao, and J. A. Frangos Temporal Gradients in Shear, but Not Spatial Gradients, Stimulate Endothelial Cell Proliferation Circulation, May 22, 2001; 103(20): 2508 - 2513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Garcia-Cardena, J. Comander, K. R. Anderson, B. R. Blackman, and M. A. Gimbrone Jr. Inaugural Article: Biomechanical activation of vascular endothelium as a determinant of its functional phenotype PNAS, April 10, 2001; 98(8): 4478 - 4485. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Miwa, T. Sasaguri, H. Inoue, Y. Taba, A. Ishida, and T. Abumiya 15-Deoxy-Delta 12,14-prostaglandin J2 Induces G1 Arrest and Differentiation Marker Expression in Vascular Smooth Muscle Cells Mol. Pharmacol., October 1, 2000; 58(4): 837 - 844. [Abstract] [Full Text]
|
|
|
|
|
|
K. Lin, P.-P. Hsu, B. P. Chen, S. Yuan, S. Usami, J. Y.-J. Shyy, Y.-S. Li, and S. Chien Molecular mechanism of endothelial growth arrest by laminar shear stress PNAS, July 30, 2000; (2000) 170282597. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Taba, T. Sasaguri, M. Miyagi, T. Abumiya, Y. Miwa, T. Ikeda, and M. Mitsumata Fluid Shear Stress Induces Lipocalin-Type Prostaglandin D2 Synthase Expression in Vascular Endothelial Cells Circ. Res., May 12, 2000; 86(9): 967 - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. F. Davies Spatial Hemodynamics, the Endothelium, and Focal Atherogenesis : A Cell Cycle Link? Circ. Res., February 4, 2000; 86(2): 114 - 116. [Full Text] [PDF]
|
|
|
|
|
|
K. Lin, P.-P. Hsu, B. P. Chen, S. Yuan, S. Usami, J. Y.-J. Shyy, Y.-S. Li, and S. Chien Molecular mechanism of endothelial growth arrest by laminar shear stress PNAS, August 15, 2000; 97(17): 9385 - 9389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Brooks, P. I. Lelkes, and G. M. Rubanyi Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow Physiol Genomics, April 10, 2002; 9(1): 27 - 41. [Abstract] [Full Text] [PDF]
|
|