Pustovrh M C, Jawerbaum A, White V, Capobianco E, Higa R, Martínez N, López-Costa J J, González E
Laboratory of Reproduction and Metabolism, Center for Pharmacological and Botanical Studies, CEFyBO-CONICET, University of Buenos Aires, Paraguay, Buenos Aires, Argentina.
Reproduction. 2007 Oct;134(4):605-13. doi: 10.1530/REP-06-0267.
Matrix metalloproteinases (MMPs) play an important role in tissue remodeling that accompanies the rapid growth, differentiation, and structural changes of the placenta and several fetal organs. In the present study, we investigated whether the diabetic maternal environment may alter the regulatory homeostasis exerted by nitric oxide (NO) on MMPs activity in the feto-placental unit from rats at midgestation. We found that NADPH-diaphorase activity, which reflects the distribution and activity of NO synthases (NOS), was increased in both placenta and fetuses from diabetic rats when compared with controls. In addition, while a NO donor enhanced MMP2 and MMP9 activities, a NOS inhibitor reduced these activities in the maternal side of the placenta from control rats. This regulatory effect of NO was only observed on MMP9 in the diabetic group. On the other hand, the NO donor did not modify MMP2 and MMP9 activities, while the NOS inhibitor reduced MMP9 activity in the fetal side of both control and diabetic placentas. In the fetuses, MMP2 was enhanced by the NO donor and reduced by the NO inhibitor in both fetuses from control and diabetic rats. Overall, this study demonstrates that NO is able to modulate the activation of MMPs in the feto-placental unit, and provides supportive evidence that increased NOS activity leads to NO overproduction in the feto-placental unit from diabetic rats, an alteration closely related to the observed MMPs dysregulation that may have profound implications in the formation and function of the placenta and the fetal organs.
基质金属蛋白酶（MMPs）在组织重塑中发挥着重要作用，这种重塑伴随着胎盘和多个胎儿器官的快速生长、分化及结构变化。在本研究中，我们调查了糖尿病母体环境是否会改变一氧化氮（NO）对妊娠中期大鼠胎儿 - 胎盘单位中MMPs活性所施加的调节稳态。我们发现，与对照组相比，糖尿病大鼠胎盘和胎儿中反映一氧化氮合酶（NOS）分布及活性的NADPH - 黄递酶活性均增加。此外，虽然NO供体增强了MMP2和MMP9的活性，但NOS抑制剂降低了对照大鼠胎盘母体侧的这些活性。在糖尿病组中，NO的这种调节作用仅在MMP9上观察到。另一方面，NO供体未改变MMP2和MMP9的活性，而NOS抑制剂降低了对照和糖尿病胎盘胎儿侧的MMP9活性。在胎儿中，NO供体增强了对照和糖尿病大鼠胎儿中MMP2的活性，而NO抑制剂则降低了其活性。总体而言，本研究表明NO能够调节胎儿 - 胎盘单位中MMPs的激活，并提供了支持性证据，即NOS活性增加导致糖尿病大鼠胎儿 - 胎盘单位中NO过量产生，这种改变与观察到的MMPs失调密切相关，可能对胎盘和胎儿器官的形成及功能产生深远影响。
