Abstract-Preeclampsia (PE) is a life-threatening, pregnancy-induced disease and a leading cause of maternal and fetal morbidity and mortality. Despite considerable research, the causes of PE remain unclear, and there is no effective treatment. Studies in animal models that resemble this complex pregnancy-related disorder may help to identify possible therapies for PE. Complement component C1q has an important role in trophoblast migration, spiral arteries remodeling, and normal placentation. Here we show that pregnant C1q-deficient (C1q Ϫ/Ϫ ) mice recapitulate the key features of human PE: hypertension, albuminuria, endotheliosis, decreased placental vascular endothelial growth factor (VEGF) and elevated levels of soluble VEGF receptor 1 (sFlt-1) that correlate with increased fetal death. In addition, decreased blood flow and increased oxidative stress are observed in placentas from C1q Ϫ/Ϫ mice. Treatment of C1q Ϫ/Ϫ mice with pravastatin restored trophoblast invasiveness, placental blood flow, and angiogenic balance and, thus, prevented the onset of PE. Serum-soluble receptors for VEGF-1 levels were reduced and placental VEGF levels were significantly increased in C1q Ϫ/Ϫ mice treated with pravastatin compared with untreated C1q Ϫ/Ϫ mice (VEGF: 1067Ϯ171 versus 419Ϯ194 pg/mL; PϽ0.01). Pravastatin treatment reduced hypertension (change in mean arterial pressure: 1Ϯ1 versus 18Ϯ3 mm Hg in C1q Ϫ/Ϫ untreated mice), and albuminuria (of creatinine) was reduced from 820Ϯ175 to 117Ϯ45 g/mg (both PϽ0.01). Renal damage and endothelial dysfunction were significantly attenuated with pravastatin. This model that highlights the causative role of impaired trophoblast invasion in the pathogenesis of PE allowed us to identify pravastatin as a good therapeutic option to prevent PE. Key Words: mouse model Ⅲ preeclampsia Ⅲ trophoblast invasion Ⅲ complement Ⅲ pravastatin P reeclampsia (PE), a pregnancy-specific, multisystemic disorder, is a leading cause of maternal and perinatal mortality and morbidity. 1 Because PE only occurs during pregnancy and its symptoms resolve after delivery, the placenta is thought to be crucial to the development of the disease. Indeed, several studies suggested that a defective trophoblast invasion and abnormal placentation are some of the underlying mechanisms of PE. 2,3 Conversion of the maternal spiral arteries into larger competent vessels is one of the essential steps in the development of the normal placenta. This process is apparently dependent on the invasion by trophoblasts of the subendometrial area and the spiral arteries. PE is characterized by shallow trophoblast invasion and unconverted narrow spiral arteries that leads to placental dysfunction and endothelial injury that eventually manifest as maternal hypertension and proteinuria. 4 The study of PE in women is of critical importance; however, studies in humans have obvious limitations that prevent investigation of many pathophysiological mechanisms and that often limit the ability to establish cause-andeffect relationships in pregnant...

BackgroundPre-eclampsia, a pregnancy-specific multisystemic disorder is a leading cause of maternal and perinatal mortality and morbidity. This syndrome has been known to medical science since ancient times. However, despite considerable research, the cause/s of preeclampsia remain unclear, and there is no effective treatment. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment.Methodology/Principal FindingsHere we show that the CBA/J x DBA/2 mouse model of recurrent miscarriage is also a model of immunologically-mediated preeclampsia (PE). DBA/J mated CBA/J females spontaneously develop many features of human PE (primigravidity, albuminuria, endotheliosis, increased sensitivity to angiotensin II and increased plasma leptin levels) that correlates with bad pregnancy outcomes. We previously reported that antagonism of vascular endothelial growth factor (VEGF) signaling by soluble VEGF receptor 1 (sFlt-1) is involved in placental and fetal injury in CBA/J x DBA/2 mice. Using this animal model that recapitulates many of the features of preeclampsia in women, we found that pravastatin restores angiogenic balance, ameliorates glomerular injury, diminishes hypersensitivity to angiotensin II and protects pregnancies.Conclusions/SignificanceWe described a new mouse model of PE, were the relevant key features of human preeclampsia develop spontaneously. The CBA/J x DBA/2 model, that recapitulates this complex disorder, helped us identify pravastatin as a candidate therapy to prevent preeclampsia and its related complications. We recognize that these studies were conducted in mice and that clinical trials are needed to confirm its application to humans.