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

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 x 10(5) 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.

Response of arterial smooth muscle cells to laminar flow.

This study was designed to determine whether laminar flow influences the proliferation rate and morphology of smooth muscle cells (SMC) in culture. Bovine aortic SMC were subjected to a shear stress of 6 dyne/cm2. The control group was subjected to similar incubation conditions without flow. Flow cytometry demonstrated decreased proliferation rate in SMC subjected to laminar flow. This phenomenon was still evident 24 hours after flow cessation. SMC were examined by light and electron microscopy. SMC subjected to laminar flow aligned along the direction of flow assuming a spheric morphology. These changes were reversible after a 48-hour resting period. The degree of organization of actin, tubulin and other microfilaments was evaluated by indirect immunofluorescence. SMC subjected to shear stress showed a clear reorganization of the cytoskeleton with expression of stress fibres. These changes were reversible after a 48-hour resting period. These findings may contribute to understanding the mechanisms by which SMC in vivo respond to forces generated by blood flowing under pressure.

Ten-year trends in Canada for selected operations.

Of 16 operations common in Canada the national rates over a 10-year period for the 9 discretionary procedures varied much more than those for the nondiscretionary operations. The rates of tonsillectomy and adenoidectomy, hemorrhoidectomy, varicose vein stripping and appendectomy decreased substantially, whereas those of extraction of lens, cesarean section and colectomy increased. The rates of hysterectomy and cholecystectomy first increased and then decreased. With the exception of Newfoundland the provinces generally followed these trends. Neither the Canadian nor the provincial rates were significantly associated with the availability of hospital beds or surgeons. Factors other than resources probably accounted for much of the variation among the provinces.

Modulation of arterial smooth muscle cell growth by haemodynamic forces.

To define the correlation between flow dynamics and the proliferation of arterial smooth muscle cells (SMCs), bovine arterial SMC were subjected to increasing laminar flow shear stress in an in vitro system. Smooth muscle cells were seeded in a fibronectin-coated polystyrene cylinder at 5 x 10(5) cells/tube. The experimental groups were subjected to increasing shear stress (3, 6, 9 dyn cm-2) for a 24-h period. The control group was subjected to similar incubation conditions without flow. Shear stress reduced significantly (p less than 0.01) the 24-h incorporation of tritiated thymidine and cell proliferation. This effect was proportional to the level of shear stress and was still evident 24 h after flow cessation. Flow cytometry demonstrated a lower percentage of SMCs in S-phase with increasing shear stress. Extrapolation of these findings to the clinical setting might explain how unphysiological shear stress can predispose to the abnormal proliferation rate of SMCs and early plaque formation.

Five-year study of surgical rates in Ontario's counties.

The surgical rates for eight operations (hysterectomy, tonsillectomy/adenoidectomy, cholecystectomy, prostatectomy, appendectomy, mastectomy, colectomy and cesarean section) done in Ontario's 44 counties from 1973 to 1977 were examined. There was considerable variation among the counties for all the operations studied, although the degree of intercounty variation decreased over the 5 years. Differences in resources (hospital beds and surgeons) explained little of the variation in the rates, but this may be because people crossed county lines for certain operations. Although some counties had consistently high or low rates for individual operations during the 5-year period, only four had consistently high rates for four or more operations, and only five had consistently low rates for four or more. The five counties with teaching health science centres had the highest ratios of specialists and surgeons to population, and, with the exception of one county in 1973, had above-average numbers of hospital beds. Despite the greater resources in these counties, their residents had consistently low rates for cholecystectomy, appendectomy, mastectomy and tonsillectomy/adenoidectomy. However, three of these counties had the highest rates for cesarean section. The variation in the rates is likely due to lack of agreement about indications for surgery or to variation in the use of technology rather than to differences in the incidence or prevalence of disorders.