Abstract-Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) and endothelin -1 (ET-1) are suggested to be important links between placental ischemia and hypertension during preeclampsia. Activation of the angiotensin II type 1 receptor (AT1R) increases endothelial cell production of ET-1; however, the importance of ET-1 in response to AT1-AA-mediated AT1 R activation during preeclampsia is unknown. Furthermore, the role of AT1-AA-mediated increases in blood pressure during pregnancy remains unclear. The objective of this study was to test the hypothesis that AT1-AA, increased to levels observed in preeclamptic women and placental ischemic rats, increases mean arterial pressure (MAP) by activation of the ET-1 system. Chronic infusion of purified rat AT1-AA into normal pregnant (NP) rats for 7 days increased AT1-AA from 0.68Ϯ0.5 to 10.88Ϯ1.1 chronotropic units (PϽ0.001). The increased AT1-AA increased MAP from 99Ϯ1 to 119Ϯ2 mm Hg (PϽ0.001). The hypertension was associated with significant increases in renal cortices (11-fold) and placental (4-fold) ET-1. To determine whether ET-1 mediates AT1-AA-induced hypertension, pregnant rats infused with AT1-AA and NP rats were treated with an ET A receptor antagonist. MAP was 100Ϯ1 mm Hg in AT1-AAϩET A antagonist-treated rats versus 98Ϯ2 mm Hg in ET A antagonist-treated rats. Collectively, these data support the hypothesis that one potential pathway whereby AT1-AAs increase blood pressure during pregnancy is by an ET-1-dependent mechanism. Key Words: preeclampsia Ⅲ hypertension Ⅲ kidney Ⅲ placenta Ⅲ inflammation T he initiating event in early onset preeclampsia is postulated to involve inadequate vascularization of the subplacental decidua with reduced placental perfusion that leads to hypertension during pregnancy by mechanisms not yet elucidated. 1,2 Recent studies have suggested that the production of agonistic autoantibodies to the angiotensin II (Ang II) type I receptor (AT1-AA) may be an important link between placental ischemia and hypertension in preeclamptic women. 3-8 The AT1-AA induces signaling in vascular cells that are blocked by an AT1 receptor antagonist including activating protein-1, calcineurin, and nuclear factor kappa B activation. 3,4,7 Recent studies by Zhou et al demonstrate that immunoglobulin isolated from preeclamptic women increases systolic blood pressure 4 days after retro-orbital injection into pregnant mice. 7,8 This hypertensive response was attenuated by administration of an AT1 receptor antagonist. Although these findings suggest that AT1-AAs from preeclamptic women increases blood pressure in pregnant mice, possibly by activation of the AT1 receptor, it remains unclear by what mechanism purified AT1-AA mediates hypertension during pregnancy.We recently reported that hypertension in response to reductions in uterine perfusion pressure in pregnant rats (RUPP) is associated with increased circulating levels of the AT1-AA. 9,10 Moreover, we found that the increased blood pressure response in RUPP pregnant rats decreased ma...

Abstract-Reductions in uterine perfusion pressure (RUPP) in pregnant rats is associated with increased tumor necrosis factor-␣ (TNF-␣). This study was designed to determine the role of endogenous TNF-␣ in mediating changes in arterial pressure and endothelin-1 (ET-1) in RUPP rats. To achieve this goal we examined the effect of RUPP in the presence and absence of a TNF-␣-soluble receptor, etanerecept (0.4 mg/kg). Mean arterial pressure increased from 102Ϯ1 mm Hg in normal pregnant (NP) rats to 134Ϯ3 mm Hg (PϽ0.05) in RUPP rats. Serum TNF-␣ increased to 40Ϯ7.6 pg/mL in RUPP rats (nϭ24)

Placental ischemia is believed to be the initial event in the development of preeclampsia. Mitochondrial dysfunction is a cause of reactive oxygen species (ROS) generation and oxidative stress, however, there are not many studies examining the role of mitochondrial ROS in the pathology of preeclampsia. The purpose of this study was to not only examine the effect of placental ischemia on mitochondrial-mediated oxidative stress in reduced uterine perfusion pressure (RUPP) rat model of preeclampsia but to also examine the role of mitochondrial ROS in contributing to hypertension in response to placental ischemia. Female pregnant Sprague Dawley rats were used in this study. On gestational day 14, RUPP surgery was performed. On gestational day 19, blood pressure (mean arterial pressure) was measured, placentas and kidneys were collected from normal pregnant and RUPP rats and processed for mitochondrial respiration, ROS, and oxidative phosphorylation enzyme activities. Renal and placental complex activities, expressions and respiration rates were significantly reduced and mitochondrial ROS was increased in RUPP versus normal pregnant mitochondria. Mean arterial pressure was elevated in RUPP (n=6) compared with normal pregnant rats (n=5; 126±4 versus 103±4 mm Hg; P<0.05) and treatment with mitochondrial-specific antioxidants (MitoQ/MitoTEMPO) significantly reduced mean arterial pressure in RUPPs (n=5-10). Mitochondrial ROS was significantly elevated in endothelial cells incubated with RUPP serum compared from with normal pregnant rats, whereas serum from mito antioxidant-treated RUPP rats attenuated this response. Impaired mitochondrial function and vascular, placental, and renal mitochondrial ROS play an important role in hypertension and reduced fetal weight in response to placental ischemia during pregnancy.

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Circulating factors, such as agonistic autoantibodies to the angiotensin II type 1 (AT1) receptor (AT1-AAs), and inflammatory cytokines, including tumor necrosis factor α (TNF-α), are suggested to be important links between placental ischemia and hypertension in preeclamptic women. The purpose of this study was to determine the role of placental ischemia and TNF-α in stimulating the AT1-AA and the importance of AT1 receptor activation in mediating hypertension during reductions in uterine perfusion pressure (RUPP) and chronic TNF-α excess in pregnant rats. Increased mean arterial pressure in RUPP pregnant rats (122±1 mm Hg RUPP versus 101±1 mm Hg normal pregnant [NP]; P<0.001) was associated with increased circulating TNF-α (RUPP 48±13 pg/mL versus N 8±1 pg/ mL; P<0.05) and AT1-AA (RUPP 15.3±1.6 U versus NP 0.6±0.3 U; P<0.001). Moreover, TNF-α-induced hypertension (97±2 to 112±2 mm Hg; P<0.05) in pregnant rats was associated with AT1-AA production (TNF-α rats 9.2±2.3 U versus NP rats 1.0±0.8 U; P<0.05). To determine the importance of AT1 receptor activation in mediating hypertension in RUPP-and TNF-α-treated rats, we administered an AT1 receptor antagonist to RUPP-, TNF-α-treated, and NP rats. Blood pressure responses were attenuated in RUPP rats (Δ 32 mm Hg versus Δ 20 mm Hg, NP; P<0.001), as well as in TNF-α-treated rats (Δ 10 mm Hg versus Δ 5 mm Hg, NP; P<0.05). Collectively, these data indicate that placental ischemia and TNF-α are important stimuli of AT1-AA, and activation of the AT1 receptor appears to, in part, mediate hypertension produced by RUPP and TNF-α in pregnant rats.

Reduced uterine perfusion pressure during pregnancy is an important initiating event in preeclampsia. Inflammatory cytokines are thought to link placental ischemia with cardiovascular and renal dysfunction. Supporting a role for cytokines are findings of elevated tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 plasma levels in preeclamptic women. Blood pressure regulatory systems (eg, renin-angiotensin system [RAS] and sympathetic nervous system) interact with proinflammatory cytokines, which affect angiogenic and endothelium-derived factors regulating endothelial function. Chronic reductions in placental perfusion in pregnant rats are associated with enhanced TNF-alpha and IL-6 production. Chronic infusion of TNF-alpha or 11-6 into normal pregnant rats significantly increases arterial pressure and impairs renal hemodynamics. TNF-alpha activates the endothelin system in placental, renal, and vascular tissues, and IL-6 stimulates the RAS. These findings suggest that inflammatory cytokines elevate blood pressure during pregnancy by activating multiple neurohumoral and endothelial factors.

Preeclampsia is characterized by blood pressure greater than 140/90 mmHg in the second half of pregnancy. This disease is a major contributor to preterm and low birth weight babies. The early delivery of the baby, which becomes necessary for maintaining maternal well-being, makes pre-eclampsia the leading cause for preterm labor and infant mortality and morbidity. Currently, there is no cure for this pregnancy disorder. The current clinical management of PE is hydralazine with labetalol and magnesium sulfate to slow disease progression and prevent maternal seizure, and hopefully prolong the pregnancy. This review will highlight factors implicated in the pathophysiology of preeclampsia and current treatments for the management of this disease.

Eclampsia, defined as unexplained seizure in a woman with preeclampsia, is a life-threatening complication of pregnancy with unclear etiology. Magnesium sulfate (MgSO4) is the leading eclamptic seizure prophylactic, yet its mechanism of action remains unclear. Here, we hypothesized severe preeclampsia is a state of increased seizure susceptibility due to blood-brain barrier (BBB) disruption and neuroinflammation that lowers seizure threshold. Further, MgSO4 decreases seizure susceptibility by protecting the BBB and preventing neuroinflammation. To model severe preeclampsia, placental ischemia (reduced uteroplacental perfusion pressure; RUPP) was combined with a high cholesterol diet (HC) to cause maternal endothelial dysfunction. RUPP+HC rats developed symptoms associated with severe preeclampsia, including hypertension, oxidative stress, endothelial dysfunction and fetal and placental growth restriction. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ; mg/kg) required to elicit seizure in RUPP+HC±MgSO4 and compared to normal pregnant controls (n = 6/group; gestational day 20). RUPP+HC rats were more sensitive to PTZ with seizure threshold being ∼65% lower vs. control (12.4±1.7 vs. 36.7±3.9 mg/kg PTZ; p<0.05) that was reversed by MgSO4 (45.7±8.7 mg/kg PTZ; p<0.05 vs. RUPP+HC). BBB permeability to sodium fluorescein, measured in-vivo (n = 5–7/group), was increased in RUPP+HC vs. control rats, with more tracer passing into the brain (15.9±1.0 vs. 12.2±0.3 counts/gram ×1000; p<0.05) and was unaffected by MgSO4 (15.6±1.0 counts/gram ×1000; p<0.05 vs. controls). In addition, RUPP+HC rats were in a state of neuroinflammation, indicated by 35±2% of microglia being active compared to 9±2% in normal pregnancy (p<0.01; n = 3–8/group). MgSO4 treatment reversed neuroinflammation, reducing microglial activation to 6±2% (p<0.01 vs. RUPP+HC). Overall, RUPP+HC rats were in a state of augmented seizure susceptibility potentially due to increased BBB permeability and neuroinflammation. MgSO4 treatment reversed this, increasing seizure threshold and decreasing neuroinflammation, without affecting BBB permeability. Thus, reducing neuroinflammation may be one mechanism by which MgSO4 prevents eclampsia during severe preeclampsia.