Li Wei, Mata Karina M, Mazzuca Marc Q, Khalil Raouf A
Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, United States.
Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, United States.
Biochem Pharmacol. 2014 Jun 1;89(3):370-85. doi: 10.1016/j.bcp.2014.03.017. Epub 2014 Apr 3.
Preeclampsia is a complication of pregnancy manifested as maternal hypertension and often fetal growth restriction. Placental ischemia could be an initiating event, but the linking mechanisms leading to hypertension and growth restriction are unclear. We have shown an upregulation of matrix metalloproteinases (MMPs) during normal pregnancy (Norm-Preg). To test the role of MMPs in hypertensive-pregnancy (HTN-Preg), maternal and fetal parameters, MMPs expression, activity and distribution, and collagen and elastin content were measured in uterus, placenta and aorta of Norm-Preg rats and in rat model of reduced uteroplacental perfusion pressure (RUPP). Maternal blood pressure was higher, and uterine, placental and aortic weight, and the litter size and pup weight were less in RUPP than Norm-Preg rats. Western blots and gelatin zymography revealed decreases in amount and gelatinase activity of MMP-2 and MMP-9 in uterus, placenta and aorta of RUPP compared with Norm-Preg rats. Immunohistochemistry confirmed reduced MMPs in uterus, placenta and aortic media of RUPP rats. Collagen, but not elastin, was more abundant in uterus, placenta and aorta of RUPP than Norm-Preg rats. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) decreased MMPs in uterus, placenta and aorta of Norm-Preg rats, and vascular endothelial growth factor (VEGF) reversed the decreases in MMPs in tissues of RUPP rats. Thus placental ischemia and anti-angiogenic sFlt-1 decrease uterine, placental and vascular MMP-2 and MMP-9, leading to increased uteroplacental and vascular collagen, and growth-restrictive remodeling in HTN-Preg. Angiogenic factors and MMP activators may reverse the decrease in MMPs and enhance growth-permissive remodeling in preeclampsia.
子痫前期是一种妊娠并发症，表现为母体高血压，常伴有胎儿生长受限。胎盘缺血可能是起始事件，但导致高血压和生长受限的相关机制尚不清楚。我们已经表明，在正常妊娠（Norm-Preg）期间基质金属蛋白酶（MMPs）上调。为了测试MMPs在高血压妊娠（HTN-Preg）中的作用，我们测量了正常妊娠大鼠以及子宫胎盘灌注压降低（RUPP）大鼠模型的子宫、胎盘和主动脉中的母体和胎儿参数、MMPs表达、活性和分布，以及胶原蛋白和弹性蛋白含量。与正常妊娠大鼠相比，RUPP大鼠的母体血压更高，子宫、胎盘和主动脉重量以及窝仔数和幼仔体重更低。蛋白质免疫印迹法和明胶酶谱分析显示，与正常妊娠大鼠相比，RUPP大鼠子宫、胎盘和主动脉中MMP-2和MMP-9的量和明胶酶活性降低。免疫组织化学证实RUPP大鼠子宫、胎盘和主动脉中膜的MMPs减少。与正常妊娠大鼠相比，RUPP大鼠子宫、胎盘和主动脉中的胶原蛋白含量更高，而弹性蛋白含量未增加。抗血管生成因子可溶性fms样酪氨酸激酶-1（sFlt-1）降低了正常妊娠大鼠子宫、胎盘和主动脉中的MMPs，而血管内皮生长因子（VEGF）逆转了RUPP大鼠组织中MMPs的降低。因此，胎盘缺血和抗血管生成的sFlt-1降低了子宫、胎盘和血管中的MMP-2和MMP-9，导致子宫胎盘和血管胶原蛋白增加，以及高血压妊娠中的生长限制性重塑。血管生成因子和MMP激活剂可能会逆转MMPs的降低，并增强子痫前期中有利于生长的重塑。
