EMMPRIN-Mediated Induction Of Uterine And Vascular Matrix Metalloproteinases During Pregnancy And In Response To Estrogen And Progesterone

Objectives:Normal pregnancy is associated with uteroplacental and vascular remodeling in order to adapt for the growing fetus and the hemodynamic changes in the maternal circulation. We have shown an upregulation of uterine matrix metalloproteinases (MMPs) during pregnancy. However, whether the pregnancy-associated changes in MMPs are localized to the uterus or are part of generalized changes in MMPs in the feto-placental and maternal circulation is unclear. Also, the mechanisms causing the changes in uteroplacental and vascular MMPs during pregnancy are unclear.Study Design:MMP expression, activity and tissue distribution were measured in uterus, placenta and aorta of virgin, mid-pregnant (mid-Preg, day-12), and late pregnant rats (late-Preg, day-19).Results:Western blots and gelatin zymography revealed an increase in the protein amount and activity of MMP-2and-9in the uterus and aorta of late-Preg compared with mid-Preg and virgin rats. In contrast, the amount and activity of MMP-2and-9were decreased in the placenta of late-Preg compared with mid-Preg rats. The amount of extracellular MMP inducer (EMMPRIN) was increased in the uterus and aorta of pregnant rats, but was less in the placenta of late-Preg than mid-Preg rats. Prolonged treatment of the uterus or aorta of virgin rats with17β-estradiol and progesterone increased the expression of EMMPRIN, and the expression and activity of MMP-2and-9. Treatment of the uterus and aorta with EMMPRIN neutralizing antibody prevented the sex hormone-induced increase in MMP-2and-9expression and activity. Immunohistochemistry revealed that the amount of MMP-2and-9and EMMPRIN were increased in the uterus and aorta of pregnant rats, but decreased in the placenta of late-Preg versus mid-Preg rats.Conclusions:The pregnancy-associated upreguation of uterine MMPs is paralleled by increased expression and activity of vascular MMPs, and both appear to be mediated by EMMPRIN and induced by estrogen and progesterone, suggesting similar effects of MMPs in uterine and vascular tissues. The decrease in MMPs expression and activity and EMMPRIN expression in the placenta of late pregnant rats suggest different effects of MMPs in the feto-placental circulation during late pregnancy.