Effect of inhibition of matrix metalloproteinases on endometrial decidualization and implantation in mated rats.
Implantation of the embryo into the endometrium is a highly regulated event that is critical for establishment of pregnancy. Molecules involved in this process provide potential targets for post-coital contraception. The aims of this study were to determine whether matrix metalloproteinases (MMPs) are present at implantation sites in rats and whether administration of a broad-based inhibitor of MMPs could inhibit embryo implantation. Uterine extracts from non-pregnant rats and from rats on days 3-9 of pregnancy were examined for the presence of MMPs. Doxycycline (5 or 15 mg day-1) was administered by gavage to rats from the day of mating (day 0) to day 7 of pregnancy and the uterus was examined for implantation sites. A number of MMPs were present in all uterine samples. MMP-2 reached a peak on day 3, whereas the highest expression of MMP-7 occurred on day 7. MMP-13 and MMP-3 were present in smaller amounts. MMP-9 was detectable only on day 9. Treatment of rats with doxycycline had no effect on the number of implantation sites or on the total uterine mass. However, in treated rats, the process of decidualization was impaired and both the width and length of the decidual zone was reduced, resulting in a decrease in total decidual area from 1.20 +/- 0.07 to 0.91 +/- 0.07 mm2 (mean +/- SEM, controls versus doxycycline treated, P < 0.02). It is concluded that administration of MMP inhibitors during early pregnancy retards decidual development, but does not block implantation.
Rechtman
M P
MP
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.
Zhang
J
J
Salamonsen
L A
LA
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003656:Decidua / Q000033:anatomy & histology / Q000187:drug effects*; D003720:Densitometry; D004318:Doxycycline / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D010064:Embryo Implantation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005865:Gestational Age; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D019278:Matrix Metalloproteinase 3 / Q000032:analysis; D020783:Matrix Metalloproteinase 7 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D014599:Uterus / Q000201:enzymology
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline