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 vascularremodeling in order to adapt for the growing fetus and the hemodynamic changes in thematernal circulation. We have shown an upregulation of uterine matrix metalloproteinases(MMPs) during pregnancy. However, whether the pregnancy-associated changes in MMPsare localized to the uterus or are part of generalized changes in MMPs in the feto-placentaland maternal circulation is unclear. Also, the mechanisms causing the changes inuteroplacental and vascular MMPs during pregnancy are unclear.Study Design: MMP expression, activity and tissue distribution were measured inuterus, placenta and aorta of virgin, mid-pregnant (mid-Preg, day-12), and late pregnantrats (late-Preg, day-19).Results: Western blots and gelatin zymography revealed an increase in the proteinamount and activity of MMP-2and-9in the uterus and aorta of late-Preg compared withmid-Preg and virgin rats. In contrast, the amount and activity of MMP-2and-9weredecreased in the placenta of late-Preg compared with mid-Preg rats. The amount ofextracellular MMP inducer (EMMPRIN) was increased in the uterus and aorta of pregnantrats, but was less in the placenta of late-Preg than mid-Preg rats. Prolonged treatment of theuterus or aorta of virgin rats with17-estradiol and progesterone increased the expressionof EMMPRIN, and the expression and activity of MMP-2and-9. Treatment of the uterusand aorta with EMMPRIN neutralizing antibody prevented the sex hormone-inducedincrease in MMP-2and-9expression and activity. Immunohistochemistry revealed that theamount of MMP-2and-9and EMMPRIN were increased in the uterus and aorta ofpregnant rats, but decreased in the placenta of late-Preg versus mid-Preg rats.Conclusions: The pregnancy-associated upreguation of uterine MMPs is paralleled byincreased expression and activity of vascular MMPs, and both appear to be mediated byEMMPRIN and induced by estrogen and progesterone, suggesting similar effects of MMPs in uterine and vascular tissues. The decrease in MMPs expression and activity andEMMPRIN expression in the placenta of late pregnant rats suggest different effects ofMMPs in the feto-placental circulation during late pregnancy.