Matrix Metallopeptidase 9 Promotes Contraction in Human Uterine Myometrium

Matrix metallopeptidase 9 (MMP9) is a secreted zinc-dependent peptidase known for extracellular remodeling. MMP9 is elevated in tissues from women experiencing preterm labor, and previous research has shown that the addition of combined matrix metallopeptidases 2 and 9 (MMP2/9) enhances uterine contractions. We hypothesized that adding MMP9 alone would enhance myometrial contractions and that specific MMP9 inhibition would suppress uterine contractions. In myometrial tissue from women undergoing term Caesarean sections, we observed an increased contractile response as measured by area under the curve over time in tissues treated with MMP9 compared to vehicle-treated controls (p = 0.0003). This effect was primarily due to increased contraction frequency in MMP9-treated tissues compared to controls (p < 0.0001). Specific inhibition of MMP9 with the highly selective MMP9 inhibitor 1 (AG-L-66085) reduced contractile responses in myometrial tissues from pregnant women. We observed a reduction in the oxytocin-induced contractile response as measured by area under the curve over time (p < 0.0001) and contraction amplitude (p < 0.0068) in AG-L-66085-treated tissues compared to vehicle-treated controls. To determine the effects of MMP9 inhibition in the absence of exogenous oxytocin, we tested the effects of AG-L-66085 on spontaneous contractions. The area under the curve (p = 0.0415) and amplitude (p = 0.0354) of spontaneous contractions were reduced in response to 1 mu M AG-L-66085, and the inhibitory effects increased as the AG-L-66085 concentration increased. Together, these data support the hypothesis that elevated MMP9 promotes myometrial contractions and labor, while its inhibition promotes relaxation.