Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy.

Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. To test the hypothesis that regional differences in angiogenic balance and matrix metalloproteinases (MMPs) underlie regional uteroplacental vascularization and feto-placental development, we compared fetal and placental growth, and placental and myoendometrial vascularization in the proximal, middle and distal regions of the uterus (in relation to the iliac bifurcation) in normal pregnant (Preg) and RUPP rats. Maternal blood pressure and plasma anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1)/placenta growth factor (PIGF) ratio were higher, and average placentae number, placenta weight, litter size, and pup weight were less in RUPP than Preg rats. The placenta and pup number and weight were reduced, while the number and diameter of placental and adjacent myoendometrial arteries, and MMP-2 and MMP-9 levels/activity were increased, and sFlt-1/PlGF ratio was decreased in distal vs proximal uterus of Preg rats. In RUPP rats, the placenta and pup number and weight, the number and diameter of placental and myoendometrial arteries, and MMP-2 and -9 levels/activity were decreased, and sFlt-1/PlGF ratio was increased in distal vs proximal uterus. Treatment with sFlt-1 or RUPP placenta extract decreased MMP-2 and MMP-9 in distal segments of Preg uterus, and treatment with PIGF or Preg placenta extract restored MMP levels in distal segments of RUPP uterus. Thus, in addition to the general reduction in placental and fetal growth during uteroplacental ischemia, localized angiogenic imbalance and diminished MMP-2 and MMP-9 could cause further decrease in placental and myoendometrial vascularization and placental and fetal growth in distal vs proximal uterus of HTN-Preg rats. Regional differences in uteroplacental perfusion, angiogenic balance and MMPs could be a factor in the incidence of preeclampsia in multiple pregnancy.

Dias-Junior CA ，Chen J ，Cui N ，Chiang CL ，Zhu M ，Ren Z ，Possomato-Vieira JS ，Khalil RA ... -  《-》

Altered matrix metalloproteinase-2 and -9 expression/activity links placental ischemia and anti-angiogenic sFlt-1 to uteroplacental and vascular remodeling and collagen deposition in hypertensive pregnancy.

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.

Li W ，Mata KM ，Mazzuca MQ ，Khalil RA ... -  《-》

Placental growth factor reverses decreased vascular and uteroplacental MMP-2 and MMP-9 and increased MMP-1 and MMP-7 and collagen types I and IV in hypertensive pregnancy.

Ren Z ，Cui N ，Zhu M ，Khalil RA ... -  《-》

Decreased uterine vascularization and uterine arterial expansive remodeling with reduced matrix metalloproteinase-2 and -9 in hypertensive pregnancy.

Lin C ，He H ，Cui N ，Ren Z ，Zhu M ，Khalil RA ... -  《-》

Increased vascular and uteroplacental matrix metalloproteinase-1 and -7 levels and collagen type I deposition in hypertension in pregnancy: role of TNF-α.

Preeclampsia is a pregnancy-related disorder manifested as maternal hypertension in pregnancy (HTN-Preg) and fetal growth restriction. Placental ischemia could be an initiating event that leads to abnormal vascular and uteroplacental remodeling in HTN-Preg; however, the molecular targets and intermediary mechanisms involved are unclear. We tested the hypothesis that placental ischemia could target vascular and uteroplacental matrix metalloproteinases (MMPs) through an inflammatory cytokine-mediated mechanism. MMP levels and distribution were measured in the aorta, uterus, and placenta of normal pregnant (Preg) rats and pregnant rats with reduced uterine perfusion pressure (RUPP). Maternal blood pressure was higher and the litter size and pup weight were lower in RUPP compared with Preg rats. Gelatin zymography showed prominent uterine MMP-2 and MMP-9 activity that was dependent on the amount of loaded protein. At saturating protein loading, both gelatin and casein zymography revealed two additional bands corresponding to MMP-1 and MMP-7 that were greater in the aorta, uterus, and placenta of RUPP compared with Preg rats. Western blots and immunohistochemistry confirmed increased MMP-1 and MMP-7 in the aorta, uterus, and placenta of RUPP versus Preg rats. The levels of MMP-1 and MMP-7 substrate collagen type I were greater in tissues of RUPP compared with Preg rats. In organ culture, TNF-α increased MMP-1 and MMP-7 in the aorta, uterus, and placenta of Preg rats, and a TNF-α antagonist prevented the increases in MMPs in tissues of RUPP rats. Thus, placental ischemia, possibly through TNF-α, increases vascular and uteroplacental MMP-1 and MMP-7, which, in turn, alter collagen deposition and cause inadequate tissue remodeling in HTN-Preg. Cytokine antagonists may reverse the increase in MMP-1 and MMP-7 expression/activity and, in turn, restore proper vascular and uteroplacental remodeling in HTN-Preg and preeclampsia.NEW & NOTEWORTHY The molecular mechanisms of preeclampsia are unclear, making it difficult to predict, prevent, or manage the pregnancy-associated disorder. This study showed that placental ischemia, possibly through the release of TNF-α, causes increases in the levels of matrix metalloproteinase (MMP)-1 and MMP-7, which could alter collagen deposition and cause inadequate uteroplacental and vascular remodeling in hypertension in pregnancy. The data suggest that targeting MMP-1 and MMP-7 and their upstream modulators, such as TNF-α, could provide a new approach in the management of hypertension in pregnancy and preeclampsia.

Li W ，Cui N ，Mazzuca MQ ，Mata KM ，Khalil RA ... -  《-》