Original communication| Volume 113, ISSUE 6, P691-699, June 1993

Shear stress modulates the proliferation rate, protein synthesis, and mitogenic activity of arterial smooth muscle cells

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      Background. The aim of this study was to determine the correlation between hemodynamic forces and proliferation of smooth muscle cells (SMC).
      Methods. Bovine arterial SMC were seeded in a fibronectin-coated polystyrene cylinder at 5 × 105 cells/tube and allowed to reach confluence and to adhere for 48 hours. The experimental groups were subjected to a laminar flow of 150 ml/min (9 dyne/cm2), 100 ml/min (6 dyne/cm2), and 50 ml/min (3 dyne/cm2) for 24 hours. The control group was subjected to similar incubation conditions without flow. The cells in the experiments remained attached and viable. All experiments were performed in triplicate or more.
      Results. Shear stress significantly reduced (p < 0.001) the 24-hour incorporation of tritiated thymidine and cell proliferation. This effect was proportional to the level of shear stress and was still evident 24 hours after flow cessation. Results of flow cytometry confirmed a lower percentage of SMC in S phase with increasing shear stress. Synthesis of cell-associated proteins was increased twofold (p < 0.01) in SMC subjected to laminar flow. SMC subjected to shear stress released a higher quantity of mitogens, including a platelet-derived growth factor (PDGF)-like substance as detected by immunologic testing. Fifty percent volume per volume conditioned serum-free medium from SMC subjected to shear stress increased threefold the tritiated thymidine uptake in PDGF receptor-bearing Swiss 3T3 cells as compared with conditioned serum-free medium from control SMC not subjected to shear stress and twelvefold as compared with standard control. The release of mitogens was proportional to the level of shear stress and was still evident 24 hours after flow cessation. The mitogenic activity was partially reduced (30%, p < 0.01) by an excess of monospecific anti-PDGF antibody.
      Conclusions. We conclude that (1) increasing shear stress inhibits SMC proliferation and stimulates the synthesis of cell-associated proteins and the release of mitogens and (2) decreasing shear stress facilitates proliferation of SMC. Thus, in situations of arterial flow separation, the increased release of mitogens from SMC subjected to high shear stress and the increased proliferation rate and susceptibility to mitogens of SMC subjected to very low shear stress may generate a critical condition that predisposes to the development of atherosclerosis with early plaque formation in regions of low-flow shear stress.
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        • Glagov S
        Hemodynamic risk factors: mechanical stress, mural architecture, medial nutrition and the vulnerability of arteries to atherosclerosis.
        in: Wisler RW Geer JC The pathogenesis of atherosclerosis. Williams and Watkins, Baltimore1972: 164-199
        • Benditt EP
        • Benditt JM
        Evidence for a monoclonal origin of human atherosclerotic plaques.
        in: Proc Natl Acad Sci USA. 70. 1973: 1753-1756
        • Ross R
        • Glomset J
        • Kariya B
        • Harker L
        A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro.
        in: Proc Natl Acad Sci USA. 71. 1974: 1207-1210
        • Rosenfeld ME
        • Bowen-Pope DF
        • Ross R
        Platelet-derived growth factor: morphologic and biochemical studies of binding, internalization, and degradation.
        J Cell Physiol. 1984; 121: 263-274
        • Ross R
        • Raines EW
        • Bowen-Pope DF
        The biology of platelet-derived growth factor.
        Cell. 1986; 46: 155-169
        • Seifert RA
        • Schwartz SM
        • Bowen-Pope DF
        Developmentally regulated production of platelet-derived growth factor-like molecules.
        Nature. 1984; 311: 669-671
        • Waterfield MD
        • Scrace GT
        • Whittle N
        • et al.
        Platelet-derived growth factor is structurally related to the putative transforming protein p28 sis of simian sarcoma virus.
        Nature. 1983; 304: 35-39
        • Sjolund M
        • Hedin U
        • Sejersen T
        • Heldin CH
        • Thyberg J
        Arterial smooth muscle cells express platelet derived growth factor (PDGF) A chain mRNA, secrete a PDGF-like mitogen, and bind exogenous PDGF in a phenotype- and growth state-dependent manner.
        J Cell Biol. 1988; 106: 403-413
        • Gronwald RGK
        • Grant FJ
        • Haldeman BA
        • et al.
        Cloning and expression of a cDNA coding for the human platelet-derived growth factor receptor: evidence for more than one receptor class.
        in: Proc Natl Acad Sci USA. 85. 1988: 3435-3439
        • Heldin CH
        • Westermark B
        • Wasteson A
        Specific receptors for platelet-derived growth factors on cells derived from connective tissue and glia.
        in: Proc Natl Acad Sci USA. 78. 1981: 3664-3668
        • Nilsson J
        • Thyberg J
        • Heldin CH
        • Westermark B
        • Wasteson A
        Surface binding and internalization of platelet-derived growth factor in human fibroblast.
        in: Proc Natl Acad Sci USA. 80. 1983: 5592-5596
        • Joris I
        • Zhand T
        • Nunneri JJ
        • Krolikowski FJ
        • Majno G
        Studies on the pathogenesis of atherosclerosis. I Adhesion and emigration of mononuclear cells in the aorta of hypercholesterolemic rats.
        Am J Pathol. 1983; 113: 341-358
        • Faggiotto A
        • Ross R
        • Harker L
        Studies of hypercholesterolemia in the nonhumane primate I. Changes that lead to fatty streak formation.
        Arteriosclerosis. 1984; 4: 323-340
        • Reidy MA
        A reassessment of endothelial injury and arterial lesion formation.
        Lab Invest. 1985; 53: 513-520
        • Walker LN
        • Bowen-Pope DF
        • Reidy MA
        Production of platelet-derived growth factor-like molecules by cultured arterial smooth muscle cells accompanies proliferation after arterial injury.
        in: Proc Natl Acad Sci USA. 83. 1986: 7311-7315
        • Barrett TB
        • Benditt EP
        Sis (platelet-derived growth factor b chain) gene transcript levels are elevated in human atherosclerotic lesions compared to normal artery.
        in: Proc Natl Acad Sci USA. 84. 1987: 1099-1103
        • Libby P
        • Warner SJC
        • Salomon RN
        • Birinyi LK
        Production of platelet-derived growth factor-like mitogen by smooth-muscle cells from human atheroma.
        N Engl J Med. 1988; 318: 1493-1498
        • Nillson J
        • Sjolund M
        • Palmberg L
        • Thyberg J
        • Heldin CH
        Arterial smooth muscle cells in primary culture produce a platelet-derived growth factor-like protein.
        in: Proc Natl Acad Sci USA. 82. 1985: 4418-4422
        • Majesky MW
        • Benditt EP
        • Schwartz SM
        Expression and developmental control of platelet-derived growth factor A-chain and B-chain/Sis genes in rat aortic smooth muscle cells.
        in: Proc Natl Acad Sci USA. 85. 1988: 1524-1528
        • Sejersen T
        • Betsholtz C
        • Sjolund M
        • Heldin CH
        • Westermark B
        • Thyberg J
        Rat skeletal myoblasts and arterial smooth muscle cells express the gene for the A chain but not the gene for the B chain (C sis) of platelet-derived growth factor (PDGF) and produce a PDGF-like protein.
        in: Proc Natl Acad Sci USA. 83. 1986: 6844-6848
        • Langone JJ
        I125 protein A: a tracer for general use in immunoassay.
        J Immunol Methods. 1978; 24: 269-274
        • Leung DY
        • Glacov S
        • Mathews MB
        Cyclic stretching stimulates synthesis of matrix components by arterial smooth muscle cells in vitro.
        Science. 1976; 191: 475-477
        • Buck RC
        Behaviour of vascular smooth muscle cells during repeated stretching of the substratum in vitro.
        Atherosclerosis. 1983; 46: 217-223
        • Davies PF
        • Dewey F
        • Bussolari SR
        • Gardon E
        • Gimbrone MA
        Influence of hemodynamic forces on vascular endothelial function.
        J Clin Invest. 1984; 73: 1121-1129
        • Eskin SG
        • Ives CL
        • McIntire LV
        • Navarro LT
        Response of cultured endothelial cells to steady flow.
        Microvasc Res. 1984; 28: 87-94
        • Sumpio BE
        • Baines AJ
        Response of porcine aortic smooth muscle cells to cyclic tensional deformation in culture.
        J Surg Res. 1988; 44: 696-701
        • Lansman JB
        Going with the flow.
        Nature. 1988; 331: 481-482
        • Sumpio BE
        • Widmann MD
        Enhanced production of an endothelium-derived contracting factor by endothelial cells subjected to pulsatile stretch.
        Surgery. 1990; 108: 277-282
        • Libby P
        • O'Brien KV
        Culture of quiescent arterial smooth muscle cells in a defined serum-free medium.
        J Cell Physiol. 1983; 115: 217-223
        • LoGerfo FW
        • Nowak MD
        • Quist WC
        Flow studies in a model carotid bifurcation.
        Arteriosclerosis. 1981; 1: 235-241
        • Zarins CK
        • Giddens DP
        • Bharadvaj BK
        • Sottiurai VS
        • Mabon RF
        • Glacov S
        Carotid bifurcation atherosclerosis: quantitative correlation of plaque localization with flow velocity profiles and wall shear stress.
        Circ Res. 1983; 53: 502-514
        • Caro CG
        • Fitzgerald JM
        • Schroter RC
        Atheroma and arterial wall shear: observation, correlation and proposal of shear dependent mass transfer mechanisms for atherogenesis.
        in: Proc R Soc Lond. 177. 1971: 109-159
        • Jin P
        • Rahn M
        • Claesson-Welsh L
        • Heldin CH
        • Sejersen T
        Expression of PDGF A-chain and beta-receptor genes during rat myoblast differentiation.
        J Cell Biol. 1990; 110: 1665-1672
        • Clemmons DR
        • VanWyk JJ
        Evidence for a functional role of endogenously produced somatomedin-like peptides in the regulation of DNA synthesis in cultured human fibroblasts and porcine smooth muscle cells.
        J Clin Invest. 1985; 75: 1914-1918
        • Libby P
        • Warner SJ
        • Friedman GB
        Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids.
        J Clin Invest. 1988; 81: 487-498
        • Winkles JA
        • Friesel R
        • Burgess WH
        • et al.
        Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I.
        in: Proc Natl Acad Sci USA. 84. 1987: 7124-7128