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John M. B. Bradley, Mary J. Kelley, XiangHong Zhu, Ann Marie Anderssohn, J. Preston Alexander, Ted S. Acott; Effects of Mechanical Stretching on Trabecular Matrix Metalloproteinases. Invest. Ophthalmol. Vis. Sci. 2001;42(7):1505-1513.
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purpose. The homeostatic mechanisms responsible for intraocular pressure (IOP)
regulation are not understood. Studies were conducted to evaluate the
hypothesis that trabecular meshwork (TM) cells sense increases in IOP
as stretching or distortion of their extracellular matrix (ECM) and
respond by increasing ECM turnover enzymes.
methods. Flow rates were increased in perfused human anterior segment organ
cultures and the matrix metalloproteinase (MMP) levels and IOP were
evaluated. Human TMs in stationary anterior segment organ culture were
mechanically stretched, and MMP levels were analyzed. TM cells were
grown on membranes, which were then stretched, and MMP levels were
evaluated. Western immunoblots, zymography, and confocal
immunohistochemistry were used to evaluate changes in MMPs and their
tissue inhibitors, the TIMPs.
results. Doubling the flow rate in perfused human organ cultures increased
gelatinase A levels in the perfusate by 30% to 50% without affecting
gelatinase B or stromelysin levels. Immediately after doubling the flow
rate, the measured IOP doubled. However, over the next few days the IOP
gradually returned to the initial level, although the flow rate was
maintained at double the initial value. Stretching stationary organ
cultures or stretching TM cells grown on membranes resulted in similar
increases in gelatinase A without changes in gelatinase B or
stromelysin levels. The gelatinase A increases occurred between 24 and
72 hours and were approximately proportional to the degree of
stretching. Although coating the membranes with different ECM molecule
affected the gelatinase A response, the optimum response occurred when
the cells had been grown long enough to produce their own ECM. By
Western immunoblot and confocal immunohistochemistry, the
stretch-induced increases in gelatinase A were accompanied by strong
decreases in TIMP-2 levels and moderate increases in one membrane type
MMP, MT1-MMP. After mechanical stretching of the membrane, gelatinase
A, MT1-MMP and TIMP-2 all exhibited a similar punctate immunostaining
pattern over the TM cell surface.
conclusions. These results are compatible with the hypothesis that elevations in IOP
are sensed by TM cells as ECM stretch/distortion. TM cells respond by
increasing gelatinase A and MT1-MMP, while decreasing TIMP-2 levels.
This will increase ECM turnover rates, reduce the trabecular resistance
to aqueous humor outflow, and restore normal IOP levels. This
hypothesis provides a regulatory feedback mechanism for IOP
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