Increased MMPs Expression And Decreased Contraction In The Rat Myometrium During Pregnancy And In Response To Prolonged Stretch And Sex Hormones

Objectives:Normal pregnancy is associated with uterine relaxation in order to accommodate the stretch imposed by the growing fetus; however, the mechanisms underlying the relation between pregnancy-associated uterine stretch and uterine relaxation are unclear. We hypothesized that increased uterine stretch during pregnancy is associated with upregulation of matrix metalloproteinases (MMPs), which in turn cause inhibition of myometrium contraction and promote uterine relaxation.Study Design:Uteri from virgin, mid-pregnant (day12), and late-pregnant rats (day19) were isolated, and myometrium strips were prepared for measurement of isometric contraction, and MMP expression and activity using RT-PCR, Western blots, and gel zymography.Results:Oxytocin caused concentration-dependent contraction of myometrium strips that was reduced in mid-and late-pregnant rats compared to virgin rats. Pretreatment with the MMP inhibitors SB-3CT (MMP-2/MMP-9Inhibitor IV), BB-94(Batimastat), or Ro-28-2653(Cipemastat) enhanced contraction in myometrium of pregnant rats. RT-PCR, Western blots and gel zymography demonstrated increased mRNA expression, protein amount and activity of MMP-2and MMP-9in myometrium of late-pregnant>mid-pregnant>virgin rats. Prolonged stretch of myometrium strips of virgin rats under8g basal tension for18hr was associated with reduced contraction, and enhanced expression and activity of MMP-2and MMP-9, that were reversed by MMP inhibitors. Concomitant treatment of stretched myometrium of virgin rats with17β-estradiol (E2), progesterone (P4), or E2+P4was associated with further reduction in contraction and increased MMP expression and activity. MMP-2and MMP-9caused significant reduction of oxytoxcin-induced contraction of myometrium of virgin rat.Conclusions:Normal pregnancy is associated with reduced myometrium contraction and increased MMPs expression and activity. The results are consistent with the possibility that myometrium stretch and concomitant increase in sex hormones during pregnancy are associated with increased expression/activity of specific MMPs, which in turn inhibit uterine contraction and promote uterine relaxation.