Department of Pharmacology, Biosciences Institute of Botucatu, Sao Paulo State University - UNESP, Botucatu, Sao Paulo, Brazil.
Unit of Biotechnology, University of Ribeirao Preto, UNAERP, Ribeirao Preto, Sao Paulo, Brazil.
Eur J Pharmacol. 2018 Dec 5;840:60-69. doi: 10.1016/j.ejphar.2018.10.017. Epub 2018 Oct 15.
Preeclampsia is manifested as maternal hypertension and fetal growth restriction. Matrix metalloproteinases (MMPs) are involved in hypertension and doxycycline reduces blood pressure by inhibition of MMPs. Moreover, excessive levels of MMPs and reduced nitric oxide (NO) bioavailability have been related to preeclampsia. We investigated the involvement of MMPs in hypertension in pregnancy induced by Nω-Nitro-L-arginine methyl ester (L-NAME) in rats. To this end, zimography was performed to evaluate the activity of MMPs -2 and -9 in placenta, uterus and thoracic aorta, and systolic blood pressure, feto-placental development and metabolites of NO were evaluated. Also, plasma antioxidant capacity, plasma levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PLGF) were examined. Doxycycline prevented hypertensive pregnancy and significant reductions in number of pups induced by L-NAME. Low NO bioavailability was found in hypertensive pregnant rats treated (or not) with doxycycline. Increased activity of placental MMP-2 and MMP-9 and uterine MMP-2 were attenuated by doxycycline. MMP-2 activity of thoracic aorta showed no change after hypertension. Increases in PLGF with concomitant decreases in sFlt-1 levels were found with doxycycline treatment. Also, plasma antioxidant capacity was improved with doxycycline. Also, elevations of plasma antioxidant capacity were observed in hypertensive rats treated with doxycycline. Therefore, we suggest that L-NAME reduced NO and this triggered the increases in MMP-2 and -9 activities during hypertensive pregnancy. Importantly, increases in MMPs activation and angiogenic imbalance were attenuated by doxycycline and these effects were associated with decreases in systolic blood pressure.
子痫前期表现为母体高血压和胎儿生长受限。基质金属蛋白酶（MMPs）参与高血压的发生，多西环素通过抑制 MMPs 降低血压。此外，MMPs 水平升高和一氧化氮（NO）生物利用度降低与子痫前期有关。我们研究了 MMPs 在 Nω-硝基-L-精氨酸甲酯（L-NAME）诱导的大鼠妊娠高血压中的作用。为此，进行明胶酶谱分析以评估 MMPs-2 和 -9 在胎盘、子宫和胸主动脉中的活性，并评估收缩压、胎-胎盘发育和 NO 的代谢物。此外，还检测了血浆抗氧化能力、血浆可溶性 fms 样酪氨酸激酶-1（sFlt-1）和胎盘生长因子（PLGF）水平。多西环素预防了 L-NAME 诱导的高血压妊娠和胎仔数量的显著减少。在接受（或不接受）多西环素治疗的高血压妊娠大鼠中发现低水平的 NO 生物利用度。胎盘 MMP-2 和 MMP-9 的活性以及子宫 MMP-2 的活性均被多西环素减弱。胸主动脉 MMP-2 活性在高血压后无变化。多西环素治疗后，PLGF 增加，sFlt-1 水平降低。此外，多西环素治疗可改善血浆抗氧化能力。还观察到高血压大鼠血浆抗氧化能力升高。因此，我们认为 L-NAME 降低了 NO，这引发了高血压妊娠期间 MMP-2 和 -9 活性的增加。重要的是，多西环素减弱了 MMPs 激活和血管生成失衡，这些作用与收缩压降低有关。
