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Pregnant women who subsequently develop preeclampsia are highly sensitive to infused angiotensin (Ang) II; the sensitivity persists postpartum. Activating autoantibodies against the Ang II type 1 (AT1) receptor are present in preeclampsia. In vitro and in vivo data suggest that they could be involved in the disease process. We generated and purified activating antibodies against the AT1 receptor (AT1-AB) by immunizing rabbits against the AFHYESQ epitope of the second extracellular loop, which is the binding epitope of endogenous activating autoantibodies against AT1 from patients with preeclampsia. We then purified AT1-AB using affinity chromatography with the AFHYESQ peptide. We were able to detect AT1-AB both by ELISA and a functional bioassay. We then passively transferred AT1-AB into pregnant rats, alone or combined with Ang II. AT1-AB activated protein kinase C-α and extracellular-related kinase 1/2. Passive transfer of AT1-AB alone or Ang II (435 ng/kg per minute) infused alone did not induce a preeclampsia-like syndrome in pregnant rats. However, the combination (AT1-AB plus Ang II) induced hypertension, proteinuria, intrauterine growth retardation, and arteriolosclerosis in the uteroplacental unit. We next performed gene-array profiling of the uteroplacental unit and found that hypoxia- inducible factor 1α was upregulated by Ang II plus AT1-AB, which we then confirmed by Western blotting in villous explants. Furthermore, endothelin 1 was upregulated in endothelial cells by Ang II plus AT1-AB. We show that AT1-AB induces Ang II sensitivity. Our mechanistic study supports the existence of an “autoimmune-activating receptor” that could contribute to Ang II sensitivity and possible to preeclampsia.

Hypertension during preeclampsia is associated with increased maternal vascular sensitivity to angiotensin II (ANGII). This study was designed to determine mechanisms whereby agonistic autoantibodies to the ANGII type I receptor (AT1-AA) enhance blood pressure (MAP) and renal vascular sensitivity to ANGII during pregnancy. First, we examined MAP and renal artery resistance index (RARI) in response to chronic administration of ANGII or AT1-AA or AT1-AA+ANGII in pregnant rats compared to control pregnant rats. In order to examine mechanisms of heightened sensitivity in response to AT1-AA during pregnancy we examined the role of endogenous ANGII in AT1-AA infused pregnant rats, Endothelin-1 and oxidative stress in AT1-AA+ANGII treated rats. Chronic ANGII increased MAP from 95 +/−2 in NP rats to 115 +/−2 mmHg. Chronic AT1-AA increased MAP to 118+/−1 mmHg in NP rats which further increased to 123+/−2 with AT1-AA+ANGII. Increasing ANGII from (10−11-10−8) decreased Af-Art diameter 15-20% but sharply decreased Af-Art diameter 60% in AT1-AA pretreated vessels. RARI increased from 0.67 in NP rats to 0.70 with AT1-AA infusion, which was exacerbated to 0.74 in AT1-AA + ANGII infused rats. AT1-AA-induced hypertension decreased with Enalapril but was not attenuated. Both tissue ET-1 and ROS increased with AT1-AA+ANGII compared to AT1-AA alone and blockade of either of these pathways had significant effects on MAP or RARI. These data support the hypothesis that AT1-AA, via activation of ET-1 and oxidative stress and interaction with endogenous ANGII, are important mechanisms whereby MAP and renal vascular responses are enhanced during preeclampsia.

Objective: This study was conducted to determine the relationship of frontal lobe cortical thickness and basal ganglia volumes to measures of cognition in adults with sickle cell anemia (SCA).Methods: Participants included 120 adults with SCA with no history of neurologic dysfunction and 33 healthy controls (HCs). Participants were enrolled at 12 medical center sites, and raters were blinded to diagnostic group. We hypothesized that individuals with SCA would exhibit reductions in frontal lobe cortex thickness and reduced basal ganglia and thalamus volumes compared with HCs and that these structural brain abnormalities would be associated with measures of cognitive functioning (Wechsler Adult Intelligence Scale, 3rd edition). Results:

Pre-eclampsia is defined as new onset hypertension with proteinuria during pregnancy. Pre-eclampsia is also characterized by endothelial cell activation and dysfunction and intrauterine growth restriction. Preeclamptic women display a chronic inflammatory response characterized by elevated inflammatory cytokines, circulating monocytes, neutrophils, and T and B lymphocytes secreting autoantibodies that activate the angiotensin II type I receptor (AT1-AA). Although the pathophysiology of pre-eclampsia is becoming more defined, the genesis of the disease is still largely unknown. Furthermore, the only treatment for extreme forms of the disease is bed rest and administration of magnesium sulfate to sustain the pregnancy a few days prior to early delivery of the fetus, which can lead to devastating neurological and physical effects for the newborn. Administration of magnesium sulfate is routinely given without adverse effects. The focus of this review is to discuss the cascade of events leading to cytokines, specifically interleukin-6 (IL-6), in stimulating vasoactive substances such as AT1-AA (Figure 1) and to examine the mechanism whereby administration of magnesium sulfate can be beneficial during pre-eclampsia. One area is to decrease vascular resistance index parameters determined by Doppler velocimetry. Another potential area of benefit with magnesium sulfate administration may be to decrease inflammatory responses or decrease cardiovascular mechanisms stimulated by overexpression of inflammatory cytokines in response to placental ischemia or animal models of elevated IL-6 during pregnancy. Further studies identifying IL-6-driven mechanisms playing a role in the development of hypertension during pregnancy and how administration of magnesium sulfate can suppress them are critical to improve decisions affecting patient care in women with pre-eclampsia. The results of these types of studies will be advantageous to further our knowledge of the pathophysiological ramifications associated with pre-eclampsia and to further therapeutic development for this disease.

Background Preeclampsia is a multisystem disorder of pregnancy, originating in the placenta. Cytochrome P450 (CYP)-dependent eicosanoids regulate vascular function, inflammation, and angiogenesis that are mechanistically important in preeclampsia. Methods and Results We performed microarray screening of placenta and decidua (maternal placenta) from 25 preeclamptic women and 23 controls. The CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic placenta and decidua. RT-PCR confirmed the upregulation and immunohistochemistry localized CYP2J2 in trophoblastic villi and deciduas at 12 weeks and term. The CYP2J2 metabolites, 5,6-epoxyeicosatrienoic acids (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids (DHET), were elevated in preeclamptic women compared to controls in the latter two-thirds of pregnancy and after delivery. Stimulating a trophoblast-derived cell line with the preeclampsia-associated cytokine, tumor necrosis factor-α, enhanced CYP2J2 gene and protein expression. In two independent rat models of preeclampsia, reduced uterine-perfusion rat and the transgenic Ang II rat, we observed elevated EET, DHET, and preeclamptic features that were ameliorated by the CYP epoxygenase inhibitor, MsPPOH. Uterine arterial rings of these rats also dilated in response to MsPPOH. Furthermore, 5,6-EET could be metabolized to a thromboxane analog. In a bioassay, 5,6-EET increased the beating rate of neonatal cardiomyocytes. Blocking thromboxane synthesis reversed that finding and also normalized large-conductance calcium-activated potassium channel (KCa1.1) activity. Conclusion Our data implicate CYP2J2 in the pathogenesis of preeclampsia and as a potential candidate for the disturbed uteroplacental remodeling, leading to hypertension and endothelial dysfunction.

Early initiation of MP inhibits HELLP syndrome disease progression and severity.

Objective Previous investigations suggest that agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) may mediate a hypertensive response through dysregulation of the endothelin-1 system. AT1-AA induced hypertension is attenuated by AT1 receptor and/or Endothelin-1 type A receptor antagonists. This study was undertaken to determine if AT1-AA induced hypertension is associated with renal endothelial dysfunction. Study Design We compared the vascular reactivity of renal interlobar arteries from normal pregnant control rats and AT1-AA chronically infused pregnant rats in the presence and absence of endothelin type A (ETA) receptor antagonism. Renal endothelial function was tested using isolated renal interlobar arteries in a pressure myograph that were exposed to acetylcholine or sodium ntiroprusside. Results Vasodilatory responses to the endothelial dependent agonist acetylcholine were impaired in AT1-AA rats (74±10%) compared to NP controls (95±5%, p<0.05). In the presence of endothelin type A (ETA) receptor antagonism, no differences were observed between controls or the AT1-AA treated group in regard to endothelial dependent (acetylcholine) relaxation. Conclusion AT1-AA induced hypertension during pregnancy is associated with disparate renal endothelial responses to acetylcholine. The difference in renal vascular responses between AT1-AA and NP rats is abolished by ETA receptor blockade.