EMMPRIN-mediated induction of uterine and vascular matrix metalloproteinases during pregnancy and in response to estrogen and progesterone

Jul 17, 2013Biochemical pharmacology

How EMMPRIN increases tissue-remodeling enzymes in the uterus and blood vessels during pregnancy and after estrogen and progesterone

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Abstract

MMP-2 and MMP-9 levels increased in the uterus and aorta of late-pregnant rats compared to virgin and mid-pregnant rats.

Pregnancy leads to increased expression and activity of MMP-2 and -9 in both the uterus and aorta.
MMP-2 and -9 levels were decreased in the placenta of late-pregnant rats compared to mid-pregnant rats.
EMMPRIN, a protein that influences MMP levels, increased in the uterus and aorta during pregnancy but was lower in the placenta of late-pregnant rats.
Treatment with estrogen and progesterone in virgin rats raised levels of EMMPRIN, MMP-2, and MMP-9, indicating hormonal regulation.
The findings suggest a similar role for MMPs in remodeling uterine and vascular tissues during pregnancy, while their role in the placenta may decrease in late pregnancy.

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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 previously shown upregulation of uterine matrix metalloproteinases (MMPs) during pregnancy. Whether pregnancy-associated changes in MMPs are localized to the uterus or are generalized in feto-placental and maternal circulation is unclear. Also, the mechanisms causing the changes in uteroplacental and vascular MMPs during pregnancy are unclear. MMPs expression, activity and tissue distribution were measured in uterus, placenta and aorta of virgin, mid-pregnant (mid-Preg) and late pregnant (late-Preg) rats. Western blots and gelatin zymography revealed increases in MMP-2 and -9 in uterus and aorta of late-Preg compared with virgin and mid-Preg rats. In contrast, MMP-2 and -9 were decreased in placenta of late-Preg versus mid-Preg rats. Extracellular MMP inducer (EMMPRIN) was increased in uterus and aorta of pregnant rats, but was less in placenta of late-Preg than mid-Preg rats. Prolonged treatment of uterus or aorta of virgin rats with 17β-estradiol and progesterone increased the amount of EMMPRIN, MMP-2 and -9, and the sex hormone-induced increases in MMPs were prevented by EMMPRIN neutralizing antibody. Immunohistochemistry revealed that MMP-2 and -9 and EMMPRIN increased in uterus and aorta of pregnant rats, but decreased in placenta of late-Preg versus mid-Preg rats. Thus pregnancy-associated upregulation of uterine MMPs is paralleled by increased vascular MMPs, and both are mediated by EMMPRIN and induced by estrogen and progesterone, suggesting similar role of MMPs in uterine and vascular tissue remodeling and function during pregnancy. The decreased MMPs and EMMPRIN in placenta of late-Preg rats suggests reduced role of MMPs in feto-placental circulation during late pregnancy.

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EMMPRIN-mediated induction of uterine and vascular matrix metalloproteinases during pregnancy and in response to estrogen and progesterone

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