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Dynamic In Vivo Changes in Tissue Inhibitors of Metalloproteinases 1 and 2, and Matrix Metalloproteinases 2 and 9, During Prostaglandin F₂-Induced Luteolysis in Sheep¹

^a Department of Animal & Nutritional Sciences, University of New Hampshire, Durham, New Hampshire 03824 ^b Department of Animal Science, University of Connecticut, Storrs, Connecticut 06269

Prostaglandin F₂ (PGF₂) typically initiates a cascade of events that leads to the functional and structural demise of the corpus luteum. A sheep model was used in which a 1-h, systemic infusion of PGF₂ (20 µg/min) is given at midcycle. Such an infusion mimics the onset of spontaneous luteolysis by causing a transient decrease in peripheral plasma progesterone, which reaches a nadir (60% of controls) at 8 h but returns to control levels by 16–24 h. We investigated whether PGF₂ also influenced the endogenous protein levels of tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-2, and matrix metalloproteinases, MMP-2 and MMP-9, all of which have been implicated in remodeling of the extracellular matrix (ECM). Corpora lutea (Day 11) were collected at 0 h and at 1, 8, 16, and 24 h post-PGF₂ infusion (n = 3 sheep at each time). Immunoblot analysis revealed an immediate and precipitous decline in TIMP-1 (30 kDa) and TIMP-2 (19 kDa) protein levels (60% and 90%, respectively; P < 0.05) at the 1-h time point and remained depressed at 8 h (P < 0.05). Gelatin zymography and other procedures identified three MMPs (85, 70, and 64 kDa), which were shown to be the latent form of MMP-9 and the active and latent forms of MMP-2, respectively. In contrast to the rapid decrease in TIMP-1 and -2 levels, an increase in MMP-2 activity (165% of controls, P < 0.05) occurred at 8 h, which corresponded to the nadir in plasma progesterone. These early changes in TIMPs and MMPs indicate that alterations in the structure of the ECM by PGF₂ may play a hitherto unsuspected role in the subsequent process of functional luteolysis.

First decision: 16 August 2001.

¹ Supported in part by Northeast Regional Project NE-161 to P.C.W.T. and USDA grant 98–35203-6635 to J.A.M.C. This is scientific contribution 2101 from the New Hampshire Agricultural Experiment Station.

² Correspondence: Paul C.W. Tsang, University of New Hampshire, Department of Animal & Nutritional Sciences, 129 Main Street, Kendall Hall, Durham, NH 03824. FAX: 603 862 3758; pct{at}cisunix.unh.edu

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