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Preeclampsia is characterized by the development of elevated blood pressure during the second and third trimesters of pregnancy that is accompanied by end organ dysfunction. The pathogenesis of preeclampsia is multifactorial but is commonly characterized by endothelial dysfunction and the overproduction of antiangiogenic factors, including the soluble VEGF (vascular endothelial growth factor) receptor sFlt-1 (soluble Fms-like tyrosine kinase receptor 1). Previously, administration of exogenous VEGF-A, bound to a carrier protein called ELP (elastin-like polypeptide), significantly reduced free sFlt-1 levels and attenuated the hypertensive response in a rodent model of preeclampsia. However, VEGF-A administration induces multifactorial effects mediated through its direct activation of the Flk-1 receptor. In response to this, we developed a therapeutic chimera using ELP bound to VEGF-B, a VEGF isoform that binds to sFlt-1 but not to Flk-1. The purpose of this study was to evaluate the in vitro activity and pharmacological properties of ELP-VEGF-B and to test its efficacy in the reduced uterine perfusion pressure rat model of placental ischemia. ELP-VEGF-B was less potent than ELP-VEGF-A in stimulation of endothelial cell proliferation and matrix invasion, indicating that it is a weaker angiogenic driver. However, after repeated subcutaneous administration in pregnant rats, ELP-VEGF-B was maternally sequestered and reduced blood pressure when compared with saline treated animals following induction of placental ischemia (123.38±11.4 versus 139.98±10.56 mm Hg, P =0.0129). Blood pressure reduction was associated with a restoration of the angiogenic capacity of plasma from rats treated with ELP-VEGF-B. ELP-VEGF-B is a nonangiogenic, maternally sequestered protein with potential efficacy for treatment of preeclampsia.

The pregnant Dahl salt-sensitive (S) rat is an established preclinical model of superimposed spontaneous preeclampsia characterized by exacerbated hypertension, increased urinary protein excretion, and increased fetal demise. Because of the underlying immune system dysfunction present in preeclamptic pregnancies in humans, we hypothesized that the pregnant Dahl S rat would also have an altered immune status. Immune system activation was assessed during late pregnancy in the Dahl S model and compared with healthy pregnant Sprague-Dawley (SD) rats subjected to either a sham procedure or a procedure to reduce uterine perfusion pressure (RUPP). Circulating immunoglobulin and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA) and Milliplex bead assay, respectively, and percentages of circulating, splenic, and placental immune cells were determined using flow cytometry. The pregnant Dahl S rat exhibited an increase in CD4+ T cells, and specifically TNFα+CD4+ T cells, in the spleen compared with virgin Dahl S rats. The Dahl also had increased neutrophils and decreased B cells in the peripheral blood as compared with Dahl virgin rats. SD rats that received the RUPP procedure had increases in circulating monocytes and increased IFN-ɣ+CD4+ splenic T cells. Together these findings suggest that dysregulated T cell activity is an important factor in both the pregnant Dahl S rats and SD rats after the RUPP procedure.

Preeclampsia is a hypertensive disorder of pregnancy that causes significant acute and long-term risk to the mother and the baby. The multifaceted maternal syndrome is driven by overproduction of circulating anti-angiogenic factors, widespread inflammation, and endothelial dysfunction. Nuclear factor-κB (NF-κB) is a transcription factor that plays a central role in the inflammatory response. Its activity is increased in the preeclamptic placenta, and it promotes the systemic endothelial dysfunction present in preeclampsia. There is an acute need for new therapeutics targeted to the causative pathways of preeclampsia. Our group has developed a drug delivery system based on the bioengineered protein ELP (elastin-like polypeptide) that is capable of stabilizing therapeutics in the maternal circulation and preventing their placental transfer. Here we used the ELP carrier system to deliver a peptide known to inhibit the NF-κB pathway. This polypeptide, containing a cell-penetrating peptide and an NF-κB inhibitory peptide derived from the p50 nuclear localization sequence (abbreviated SynB1-ELP-p50i), blocked NF-κB activation and prevented TNF-α (tumor necrosis factor alpha)–induced endothelin production in vitro. Fusion of the p50i peptide to the SynB1-ELP carrier slowed its plasma clearance and prevented its placental transfer in pregnant rats, resulting in increased deposition in the maternal kidney, liver, and placenta relative to the free peptide. When administered in a rat model of placental ischemia, SynB1-ELP-p50i partially ameliorated placental ischemia-induced hypertension and reduced placental TNF-α levels with no signs of toxicity. These data support the continued development of ELP-delivered NF-κB inhibitors as maternally sequestered anti-inflammatory agents for preeclampsia therapy.

Preeclampsia is a common obstetrical complication, hallmarked by new-onset hypertension. Believed to result from placental insufficiency and chronic placental ischemia, the symptoms of preeclampsia are caused by release of pathogenic factors from the placenta itself, although the mechanisms of their regulation are in many cases unknown. One potential mechanism is through changes in placental epigenetic chromatin modifications, particularly histone acetylation and DNA methylation. Here, we determined the effects of chronic ischemia on global epigenetic modifications in the rodent placenta in vivo and acute hypoxia in BeWo placental trophoblast cells in vitro. Placental insufficiency via uterine artery restriction increased maternal blood pressure and fetal demise while decreasing placental and fetal mass. Global placental histone H3 acetylation levels were significantly decreased at H3 K9, K14, K18, K27, and K56. Interestingly, when BeWo-immortalized placental trophoblast cells were cultured in oxygen concentrations mimicking healthy and ischemic placentas, there was a significant increase in acetylated at K9, K18, K27, and K56. This was associated with a small but significant decrease in placental acetyl-CoA, suggesting depletion in the source of acetyl group donors. Finally, while global methylation of cytosine from placental DNA was low in both groups of animals (

Animal models have been critical in investigating the pathogenesis, mediators, and even therapeutic options for a number of diseases, including preeclampsia. Preeclampsia is the leading cause of maternal and fetal morbidity and mortality worldwide. The placenta is thought to play a central role in the pathogenesis of this disease because it releases antiangiogenic and proinflammatory factors into the maternal circulation, resulting in the maternal syndrome. Despite the deleterious effects preeclampsia has been shown to have on the mother and baby during pregnancy and postpartum, there is still no effective treatment for this disease. Although clinical studies in patients are crucial to identify the involvement of pathogenic factors in preeclampsia, there are obvious limitations that prevent detailed investigation of the quantitative importance of time-dependent mechanisms involved in this syndrome. Animal models allow investigators to perform proof-of-concept studies and examine whether certain factors found in women with preeclampsia mediate hypertension and other manifestations of this disease. In this brief review, we summarize some of the more widely studied models used to investigate pathophysiological mechanisms that are thought to be involved in preeclampsia. These include models of placental ischemia, angiogenic imbalance, and maternal immune activation. Infusion of preeclampsia-related factors into animals has been widely studied to understand the specific mediators of this disease. These models have been included, in addition to a number of genetic models involved in overexpression of the renin-angiotensin system, complement activation, and trophoblast differentiation. Together, these models cover multiple mechanisms of preeclampsia from trophoblast dysfunction and impaired placental vascularization to the excess circulating placental factors and clinical manifestation of this disease. Most animal studies have been performed in rats and mice; however, we have also incorporated nonhuman primate models in this review. Preclinical animal models not only have been instrumental in understanding the pathophysiology of preeclampsia but also continue to be important tools in the search for novel therapeutic options for the treatment of this disease.

BACKGROUND Preeclampsia is a pregnancy complication which manifests as new-onset hypertension, proteinuria, and a spectrum of other symptoms. While the underlying causes are still a subject of much debate, it is commonly believed that placental ischemia is a central cause. The ischemic placenta secretes factors which are believed to be responsible for the maternal syndrome; most notably the anti-angiogenic protein soluble fms-like tyrosine kinase 1 (sFlt-1). We have reported that induction of the carbon monoxide (CO) producing protein heme oxygenase-1 restored angiogenic imbalance and reduced blood pressure in a rat model of placental ischemia, and that CO blocks hypoxia-induced sFlt-1 production from placental tissue in vitro. We therefore hypothesized that direct administration of CO by a CO-releasing molecule (CORM) would blunt the placental ischemia-induced increase in sFlt-1 and thus the hypertension characteristic of this model. METHODS We administered a soluble CO donor molecule (CORM-3) daily i.v. in control animals or those undergoing placental ischemia from GD14. Blood pressure and renal function were measured on GD19, and angiogenic markers measured by ELISA. RESULTS Interestingly, though we found that CORM administration significantly blunted the hypertensive response to placental ischemia, there was no concomitant normalization of sFlt-1 in either the placenta or maternal circulation. We did find, however, that CORM administration caused a significant increase in glomerular filtration rate, presumably by vasodilation of the renal arteries and increased renal plasma flow. CONCLUSIONS All in all these data suggest that administration of CO by CORMs do lower blood pressure during placental ischemia mechanisms independent of changes in angiogenic balance.

Perhaps no disease of pregnancy has been more thoroughly studied than pre-eclampsia (PE), and yet despite all of our efforts we are only beginning to understand the molecular mechanisms which underpin the disease. Many people are surprised by the frequency of PE in the population, as it is believed to occur in approximately one pregnancy out of 20 in the United States, with similar rates throughout the developed world. In severe cases the disorder can progress to eclampsia, which is characterized by maternal seizures and can lead to death. PE can only be treated by ending the pregnancy, often by inducing labour prior to term, making PE a leading cause of premature birth and all of the associated health complications which accompany it. All in all, PE is one of the leading causes of maternal and fetal morbidity and mortality. It is now also becoming apparent that PE disposes both the mother and the baby to increased risk of cardiovascular disease throughout life, meaning that we still don't fully understand the long-term implications of the disease.

Preeclampsia is often characterized by high circulating levels of sFlt-1 and low VEGF and PlGF. VEGF supplementation therapy has shown promise in preclinical models, however rapid plasma clearance hampers the use of VEGF as a therapeutic. We fused human VEGF-A 121 with the Elastin-like Polypeptide (ELP) protein carrier. The objective of this study was to test the pharmacokinetics and therapeutic efficacy of ELP-VEGF when given via intravenous (IV) and subcutaneous (SC) administration routes.Fluorescently labeled ELP-VEGF was administered via daily IV (5 mg/kg/day) or SC injection (50 mg/kg/day). Plasma levels were determined by direct fluorescence measurement, and whole-body fluorescence imaging was used to determine total tissue clearance rates. The ability of SC delivered ELP-VEGF to modulate blood pressure was tested in a rat model of placental ischemia.When administered via IV injection, ELP-VEGF cleared from the plasma with an average daily half-life of 2.17±1.14 h. SC injected ELP-VEGF was absorbed into the blood and peaked within 2 hours of each injection. Tissue levels peaked 2h after each injection and remained elevated prior to the next injection, resulting in accumulation and high whole-body bioavailability. In pregnant rats, placental ischemia induced an increase in mean arterial pressure (108 ±11 vs. 122±13 mmHg, p=0.024). Daily SC injection of ELP-VEGF (50 mg/kg/day) completely prevented placental ischemia-induced increases in blood pressure (107±11 vs. 109±9 mmHg, p=ns). These results demonstrate that ELP-VEGF is bioavailable via clinically relevant administration routes and is a promising candidate agent for preeclampsia therapy.

Preeclampsia (PE) is a pregnancy-specific, multisystemic disorder that occurs in roughly 5% of pregnancies in the United States.1,2 The rates of PE in the United States have been steadily rising over the past 30 years with PE being a leading cause of maternal and fetal/neonatal morbidity and mortality.3 Women with PE, as well as their offspring, are at greater risk for chronic diseases, including cardiovascular disease (CVD) later in life.4,5 Despite being the leading cause of maternal death and a major contributor to maternal and perinatal morbidity, drug treatment to prevent PE is at best minimally effective, and current management therapies have significant limitations. In fact, at present, delivery is considered the only effective intervention for treating PE6 and even then PE may continue in the postpartum period or present de novo.7 The lack of progress in identifying new therapeutic targets for the treatment of PE is due in part to a paucity of animal models that address the heterogeneity of human PE as well as lack of understanding of basic disease mechanisms. There are no models of spontaneously developing PE in animals. Developing novel animal models to mimic human PE, identifying biomarkers to predict PE, conducting basic studies to better understand disease mechanisms, and ultimately, developing novel therapeutic strategies are clearly needed. The National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), held a workshop to examine the topic of Predicting, Preventing and Treating Preeclampsia on May 21–22, 2018, in Bethesda, MD. Speakers were chosen for expertise in general areas identified as important and cutting edge by the organizers. Specific topics discussed during the workshop were: i) pathophysiology of PE; ii) immunological origins of PE; iii) how to define subsets of PE; iv) biomarkers; v) nutritional factors; vi) genetics and epigenetics; vii) animal models; viii) collaboration, harmonization, sharing large data and samples sets in the study of PE; ix) periconceptional contributors to pathophysiology; x) clinical risk factors for PE; xi) novel therapies for the prevention and treatment of PE; xii) long-term cardiovascular consequences of PE and xiii) patient perspectives. Based on these discussions, recommendations for future research were developed in the following general areas: 1) Pathophysiology of PE; 2) Impact of PE on long-term health outcomes; 3) Biomarkers and diagnostic tools; 4) Translational research and novel treatment strategies. The purpose of this report is to summarize the scientific research recommendations arising from deliberations of the invited speakers and meeting attendees. These research recommendations are summarized in Table 1 (which is keyed to the manuscript text) and are presented in no particular order of priority. The goal of the recommendations is to provide guidance regarding future research on PE and its short- and long-term consequences. Table1: Summary of recommendations from the NIH workshop on “Predicting, Preventing and Treating Preeclampsia”

Preeclampsia (PE) is a form of gestational hypertension that complicates ∼5% of pregnancies worldwide. Over 70% of the fatal cases of PE are attributed to cerebral oedema, intracranial haemorrhage and eclampsia. The aetiology of PE originates from abnormal remodelling of the maternal spiral arteries, creating an ischaemic placenta that releases factors that drive the pathophysiology. An initial neurological outcome of PE is the absence of the autonomically regulated cardiovascular adaptations to pregnancy. PE patients exhibit sympathetic overactivation, in comparison with both normotensive pregnant and hypertensive non-pregnant females. Moreover, PE diminishes baroreceptor reflex sensitivity (BRS) beyond that observed in healthy pregnancy. The absence of the cardiovascular adaptations to pregnancy, combined with sympathovagal imbalance and a blunted BRS leads to life-threatening neurological outcomes. Behaviourally, the increased incidences of maternal depression, anxiety and post-traumatic stress disorder (PTSD) in PE are correlated to low fetal birth weight, intrauterine growth restriction (IUGR) and premature birth. This review addresses these neurological consequences of PE that present in the gravid female both during and after the index pregnancy.

Preeclampsia is a disorder of pregnancy characterized by new-onset hypertension and maternal endothelial dysfunction. Although the origins of the disease are unclear, it is believed that placental hypoxia/ischemia leads to the release of soluble factors which cause the maternal syndrome. The best characterized factor elevated in PE is soluble fms-like Tyrosine Kinase-1 (sFlt-1), a soluble splice variant of the VEGFR1 receptor which acts as a decoy receptor; and thus a VEGFA antagonist. Overproduction of this protein is believed to be a major contributor to the maternal endothelial dysfunction, causing much speculation that VEGF supplementation could be an effective supplementation could be an effective therapy. Recently we described a VEGFA chimera therapy (ELP-VEGFA) which alleviated the hypertension associated with placental ischemia in a rodent model, but also led to a dramatic increase in maternal circulating sFlt-1. Here we tested the hypothesis that chimeric VEGF would significantly increase sFlt-1 production from placental tissue in vitro. Surprisingly, there was no effect of ELP-VEGF on sFlt-1 production in either BeWo placental trophoblasts or in rodent placental tissue explants at either the mRNA or protein level. Instead, we found that vascular endothelial cells (HUVECs) responded robustly to ELP-VEGFA at the protein (6593 ± 199 vs 14547 ± 364 pg/ml, p

Preeclampsia (PE) complicates 3-5% of pregnancies with gestational hypertension, and programs later life outcomes in both mother and offspring. The unknown etiology arises from abnormal remodeling of the maternal spiral arteries, creating an ischemic placenta that releases pathogenic factors that drive the syndrome. One of these factors, soluble fms-like tyrosine kinase-1 (sFlt-1), contributes to the hypertensive response by sequestering vascular endothelial growth factor (VEGF). Currently, no effective pharmacological therapies exist for PE. With the goal of developing PE treatments that are safe for both the mother and fetus, novel therapies that target sFlt-1 are being tested in the reduced uterine perfusion pressure (RUPP) rodent model. Previously, we demonstrated that intraperitoneal administration of human VEGF-A121 fused to the bioengineered protein polymer drug carrier elastin-like polypeptide (ELP-VEGF), at a dose of 5 mg/kg/d, blocked hypertension by sequestering sFlt-1, enhanced renal nitric oxide signaling, and simultaneously prevented fetal exposure to VEGF. However, chronic intraperitoneal infusion was associated with adverse ascites production, and at the 10 mg/kg/day dose, fetal loss. In order to minimize dose-dependent side effects while retaining the therapeutic efficacy of ELP-VEGF, chronic biodistribution studies were conducted in non-pregnant female hairless Sprague-Dawley rats. ELP-VEGF was fluorescently labeled, and rats ( n =4) received a single 50 mg/kg bolus subcutaneously (SC) between the scapulae or intravenously (IV) by daily bolus injection (5 mg/kg/day) via jugular catheter. Blood draws and in vivo whole-animal imaging were conducted at specific timepoints to assess plasma levels and mean tissue polypeptide levels. Pharmacokinetic fits demonstrated a plasma half-life of 2.18 +/- 1.1 hours following IV administration, and the plasma clearance rate was consistent after each daily injection. Tissue levels accumulated over the five-day IV dosing time course. When administered SC, plasma levels peaked 3 hours after administration and cleared slowly over a 24 - 48 h period. Based on these data, the therapeutic efficacy of daily SC administration of ELP-VEGF (50 mg/kg/d) is being assessed in the RUPP model.

Preeclampsia is a pregnancy-induced hypertensive disorder resulting from abnormal placentation, which causes factors such as sFlt-1 to be released into the maternal circulation. Though anti-hypertensive drugs and magnesium sulfate can be given in an effort to moderate symptoms, the syndrome is not well controlled. A hallmark characteristic of preeclampsia, especially early-onset preeclampsia, is angiogenic imbalance resulting from an inappropriately upregulated sFlt-1 acting as a decoy receptor binding vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), reducing their bioavailability. Administration of sFlt-1 leads to a preeclamptic phenotype, and several models of preeclampsia also have elevated levels of plasma sFlt-1, demonstrating its role in driving the progression of this disease. Treatment with either VEGF or PlGF has been effective in attenuating hypertension and proteinuria in multiple models of preeclampsia. VEGF, however, may have overdose toxicity risks that have not been observed in PlGF treatment, suggesting that PlGF is a potentially safer therapeutic option. This review discusses angiogenic balance as it relates to preeclampsia and the studies which have been performed in order to alleviate the imbalance driving the maternal syndrome.

Purpose One of the most common, and most vexing, obstetric complications is preeclampsia—a major cause of maternal and perinatal morbidity. Hallmarked by new-onset hypertension and a myriad of other symptoms, the underlying cause of the disorder remains obscure despite intensive research into its etiology. Although the initiating events are not clear, one common finding in preeclamptic patients is failure to remodel the maternal arteries that supply the placenta, with resulting hypoxia/ischemia. Intensive research over the past 2 decades has identified several categories of molecular dysfunction resulting from placental hypoxia, which, when released into the maternal circulation, are involved in the spectrum of symptoms seen in these patients—in particular, angiogenic imbalance and the activation of innate and adaptive immune responses. Despite these new insights, little in the way of new treatments for the management of these patients has been advanced into clinical practice. Indeed, few therapeutic options exist for the obstetrician treating a case of preeclampsia. Pharmacologic management is typically seizure prophylaxis, and, in severe cases, antihypertensive agents for controlling worsening hypertension. Ultimately, the induction of labor is indicated, making preeclampsia a leading cause of premature birth. Here, the molecular mechanisms linking placental ischemia to the maternal symptoms of preeclampsia are reviewed, and several areas of recent research suggesting new potential therapeutic approaches to the management of preeclampsia are identified.

Introduction Preeclampsia (PE) is a multifactorial disease in which little progress has been made to develop adequate therapy. One hallmark of this disease is a rise in systemic maternal inflammatory factors, many of which signal through the NF-kB pathway. Hypothesis We hypothesize that administration of a novel NF-κB antagonist, ELP-p50i, will attenuate the hypertension and inflammation in the preclinical RUPP model of placental insufficiency. Methods Animals were received on GD11 and received the sham or RUPP surgery on GD14 along with drug or vehicle administration. On GD18, carotid catheters were placed for blood pressure measurement on GD19. Aortic ET-1 was measured by qRT-PCR using Taq primers specific for rat ET-1 and normalized to rat β-actin (Thermofisher). Placental TNF-α was measured using a commercial ELISA specific for rat TNF-α) (R&D). Results RUPP animals had significantly increased blood pressure (122.2 ± 2.56 mmHg vs 99.3 ± 3.83 mmHg, p Discussion Our data suggest that ELP-p50i is able to attenuate placental ischemia-induced hypertension and correct symptoms such as endothelial dysfunction and increased inflammation, potentially creating a therapeutic option for preeclampsia.

Introduction Placental ischemia appears to be a central causative factor in the maternal symptoms of preeclampsia. The maternal/fetal interface in the placenta is covered in a meshwork resembling the endothelial glycocalyx; consisting of proteoglycans like Syndecan-1 (SDC-1). This glycocalyx is essential for preventing immune cell adherence, and shed glycocalyx fragments are pro-inflammatory. Objective/Hypothesis We hypothesize that hypoxia/ischemia will cause degradation and shedding of the placental glycocalyx. Methods Placental ischemia was studied using the rodent RUPP model, which induces placental ischemia from GD14–19. Acute hypoxia utilized culture BeWo trophoblasts exposed at 8% or 1% oxygen for 24 h to simulate the normal or ischemic placenta respectively. SDC-1 was measured via western blot in placenta and by commercial ELISA in cell culture. Results RUPP rats showed a significant decrease in placental syndecan-1 compared to sham controls (100 ± 33% vs 67 ± 17%, p Discussion Placental ischemia and acute hypoxia both contribute to trophoblast shedding of the placental glycocalyx in a manner dependent on heparanase, MMP activity, and oxidative stress.

Introduction Preeclampsia (PE) is a multifactorial disease in which little progress has been made to develop adequate therapy. One of the etiologies of this maternal syndrome includes a rise in maternal anti-angiogenic factors; such as sFlt-1. Here we describe a novel therapeutic antagonist of sFlt-1 based on placental growth factor (PlGF). Hypothesis We hypothesize that our novel therapeutic, ELP-PlGF, will attenuate the hypertension and endothelial dysfunction in the preclinical RUPP model of placental insufficiency. Methods Animals were received on GD11 and received the sham or RUPP surgery on GD14 along with drug or vehicle administration. On GD18, carotid catheters were placed for blood pressure measurement on GD19. Western blots used serum samples with an antibody specific for PlGF (Abcam) and were normalized to the amount of serum loaded per well. Results Untreated HUVEC cells had significantly greater tube formation compared to cells treated with sFlt-1 (44.6 + 7.4 tubes/field vs 29.3 + 6.4 tubes/field, p + 4.3 tubes/field vs 44.6 + 7.4 tubes/field, p = 0.998). RUPP animals had significantly increased blood pressure compared to normal pregnant counterparts (116.7 + 1.96 mmHg vs 92.4 + 3.32 mmHg, p + 1.96 mmHg vs 105.6 + 4.70 mmHg, p = 0.051). Western blots showed a trend for decreased circulating PlGF (1.0 + 0.18 vs 0.73 + 0.11-fold change, p = 0.26, n = 4) in RUPP animals, with a near- significant trend towards increased endogenous free PlGF with ELP-PlGF administration (0.73 + 0.11 vs 1.79 + 0.35, p = 0.051, n = 4). Discussion Angiogenic imbalance is one of the best characterized contributors to the development of preeclampsia, largely lead by elevated sFlt-1. Our promising data suggest that our novel drug, ELP-PlGF, may work to correct this imbalance and potentially serve as a therapeutic for preeclampsia.

Preeclampsia is a complication of pregnancy that is marked by hypertension, proteinuria, and maternal endothelial dysfunction. A central factor in the etiology of the disease is the development of placental hypoxia/ischemia, which releases pathogenic soluble factors. There is currently no effective treatment for preeclampsia, but the phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been suggested, as PDE-5 is enriched in the uterus, and its antagonism could improve uteroplacental function. Here, we report in the reduced uterine perfusion pressure (RUPP) rat model that administration of oral sildenafil is effective in attenuating placental ischemia-induced hypertension during gestation. RUPP animals have significantly elevated arterial pressure compared with control animals (132 ± 3 vs. 100 ± 2 mmHg; P < 0.05). Administration of oral sildenafil (45 mg·kg−1·day−1) had no effect on blood pressure in control rats but decreased pressure in RUPP rats (115 ± 1 mmHg; P < 0.05). RUPP induced changes in placental sFlt-1, and vascular endothelial growth factor (VEGF) was unaffected by sildenafil administration, as was the decrease in free plasma VEGF. RUPP animals had a significant increase in medullary PDE-5/β-actin ratio (1 ± 0.14 vs. 1.63 ± 0.18; P < 0.05) expression with a resulting reduction in renal medullary cGMP (1.5 ± 0.15 vs. 0.99 ± 0.1 pmol/μg protein, P < 0.05) compared with controls. Although sildenafil had no effect on renal medullary cGMP in control animals, it significantly increased cGMP in RUPP animals (1.3 ± 0.1 pmol/μg protein; P < 0.05). These data suggest that sildenafil might provide an effective therapeutic option for the management of hypertension during preeclampsia.

Emerging evidence supports an important role for the heme oxygenase system in the maintenance of a healthy pregnancy. This review attempts to collect these wide-ranging data and summarize the recent progress in the field.New studies looking at heme oxygenase depletion in a variety of animal models have demonstrated that the heme oxygenase system is an important regulator of placental development, particularly in vascular structure. Furthermore, emerging studies demonstrate a role for heme oxygenase in the maintenance of pregnancy, especially during pathological challenge. Intriguingly, it now appears that the heme oxygenase system can be dramatically altered by pathological disorders of pregnancy, in particular preeclampsia, perhaps functionally in the symptomatic phase of the disorder. Promisingly, however, recent data suggest that induction of the heme oxygenase system, or administration of its bioactive metabolites, could provide a promising novel therapeutic approach to the management of this currently untreatable disease.Long considered a molecular housekeeping system, the heme oxygenase system is now known to be an important stress response pathway. New evidence suggests that it is also an important player in pregnancy and preeclampsia. However, the evidence now also suggests that it may provide a therapeutic approach for this common disease with few management options.

Preeclampsia is a common and serious obstetrical complication, hallmarked by new-onset hypertension and maternal endothelial dysfunction. Believed to result as a consequence of placental insufficiency and chronic placental ischemia, the symptoms of preeclampsia are caused by release of pathogenic factors from the placenta itself. A number of these factors have been identified, and it is likely that there are molecular mechanisms which remain obscure. The molecular regulation of even the known factors is often unclear. Here, we have used an established rodent model of placental ischemia which mimics many of the aspects of the human disorder to determine the direct effects of ischemia on global epigenetic modification in the placenta proper. In response to placental insufficiency, maternal blood pressure and rate of fetal demise increased significantly, while placental and fetal mass were decreased. Whole placental levels of histone H3 acetylation at K9 and K27 were increased ~2 and 3 fold respectively. Global methylation of cytosine from placental DNA was low in both groups (

Background: Preeclampsia is a major obstetrical health concern, affecting 5-8% of all pregnancies. Hallmarked by hypertension and endothelial dysfunction the origin of the disease remains obscure, though it is generally accepted that placental insufficiency/ischemia is a central cause. In response, the placenta secretes pathogenic factors, in particular the anti-angiogenic protein sFlt-1. Currently, there is no effective therapy for the management of the preeclampsia patient. We have recently produced a novel synthetic peptide based on placental growth factor (PlGF) which is maternally restricted by fusion to the synthetic carrier elastin like polypeptide (ELP). Here, we describe its in vivo pharmacokinetics and biodistribution. Methods: Fluorescently labeled ELP-PLGF was administered i.v. and blood sampled serially to determine clearance kinetics. Long-term pharmacokinetics and biodistribution was performed after subcutaneous administration of labeled peptide. Measurements were made on serially drawn blood, and in the whole animal by in vivo imaging. Results: ELP-PlGF exhibited markedly more favorable pharmacokinetics than the normal half life of PlGF, with a terminal half-life of ~10 hours as opposed to ~30 minutes for PlGF alone. Chronic administration found highest levels accumulating in placenta and kidney (two favorable targets for preeclampsia) and liver. A single subcutaneous administration at 100mg/kg resulted in sustained therapeutic plasma concentrations for over 10 days. Conclusion: These data demonstrate that ELP-PlGF has favorable pharmacokinetic and biodistribution profiles. Previous data suggest ELP-PlGF directly antagonizes sFlt-1 in culture. Future studies to assess the in vivo effectiveness of ELP-PlGF in managing placental ischemia induced hypertension and endothelial dysfunction are currently in progress. Acknowledgment: This work was supported by NIH grants R0121527 (GLB), T32HL105324 (OCL), P01HL51971, P20GM104357 (EMG), and R00HL116774 (EMG)

Purpose of review Vascular endothelial growth factors (VEGFs) influence renal function through angiogenesis, with VEGF-A being the most potent inducer of vascular formation. In the normal glomerulus, tight homeostatic balance is maintained between the levels of VEGF-A isoforms produced by podocyte cells, and the VEGF receptors (VEGFRs) expressed by glomerular endothelial, mesangial, and podocyte cells. Renal disease occurs when this homeostatic balance is lost, manifesting in the abnormal autocrine and paracrine VEGF-A/VEGFR signaling, ultrastructural glomerular and tubular damage, and impaired filtration. Recent findings Preclinical disease models of ischemic renal injury, including acute ischemia/reperfusion, thrombotic microangiopathy, and chronic renovascular disease, treated with exogenous VEGF supplementation demonstrated therapeutic efficacy. These results suggest a therapeutic VEGF-A paracrine effect on endothelial cells in the context of acute or chronic obstructive ischemia. Conversely, renal dysfunction in diabetic nephropathy appears to occur through an upregulated VEGF autocrine effect on podocyte cells, which is exacerbated by hyperglycemia. Therefore, VEGF supplementation therapy may be contraindicated for treatment of diabetic nephropathy, but specific results will depend on dose and on the specific site of VEGF delivery. A drug delivery system that demonstrates cell specificity for glomerular or peritubular capillaries could be employed to restore balance to VEGF-A/VEGFR2 signaling, and by doing so, prevent the progression to end-stage renal disease. Summary The review discusses the preclinical data available for VEGF supplementation therapy in models of renal disease.

One of the most pervasive disorders of pregnancy is preeclampsia, which is defined as new-onset hypertension presenting after the 20th week of gestation and is accompanied by increasing levels of proteinuria and often edema.1 The overall prevalence of preeclampsia is ≈8% with higher incidence in specific ethnic subpopulations, notably blacks.2,3 The disorder is predominantly a complication of primiparous women, who have a 3-fold higher incidence rate than multiparous women. There are a number of known factors that convey elevated risk of developing preeclampsia, notably elevated body mass index, and a previous incidence of preeclampsia, because women who experienced preeclampsia in previous pregnancies are 7 times more likely to exhibit preeclamptic symptoms in subsequent pregnancies than those with no history of preeclampsia.4 It has also been shown that high body mass index can double the risk of preeclampsia, and the scale of obesity correlates directly with the increase risk of developing the disorder.5 Although the link between these risk factors seem logical, there are also a number of other risk factors (maternal age, induced abortions, interpregnancy interval, and socioeconomic factors) for which the links to preeclampsia are not as clear.6 More research is warranted into the mechanistic effect of these factors in the etiology of preeclampsia. There are currently no definitive treatment options for the resolution of preeclampsia. Available interventions are confined to magnesium sulfate for the prophylaxis of seizures and the administration of one of various antihypertensive agents, although normalization of blood pressure is not normally possible, and the disease continues to progress.1 Indeed, the only effective resolution of preeclampsia is delivery of the placenta, because delivery of the fetus alone is not sufficient.7,8 It is this fact that suggested the pathological origins of the development of preeclampsia. Although …

Pre-eclampsia is a common disorder of pregnancy for which the underlying mechanism is poorly understood. A genome-wide association study has now identified a pre-eclampsia susceptibility locus located near the FLT1 gene. This study brings us a step closer to dissecting the underlying causes of pre-eclampsia.

During pregnancy, there are a number of important changes to cardiovascular function which are necessary for progression of a successful pregnancy. Additionally, preexisting cardiovascular conditions can be exacerbated by the adaptations that occur during gestation. These can present serious therapeutic challenges in the management of the cardiology patient during pregnancy. Significantly, the number of pregnant women at risk of cardiovascular complications is on the rise, so identification of risk factors that predict cardiac outcomes is essential to proper screening of the obstetrical patient. In diagnosed preexisting conditions, such as pulmonary hypertension, counseling is important prior to pregnancy. In the case of underlying disorders unmasked by pregnancy, or new-onset complications like preeclampsia, appropriate monitoring and treatment of the cardiovascular complications is warranted. Ultimately, collaborative care by both obstetricians and cardiologists is essential for the successful resolution of cardiovascular dysfunction in the obstetrical patient.

Preeclampsia is a pregnancy-induced hypertensive disorder characterized by proteinuria and widespread maternal endothelial dysfunction. It remains one of the most common disorders in pregnancy and remains one of the leading causes of maternal and fetal morbidity. Recent research has revealed that placental insufficiency, resulting in hypoxia and ischemia, is a central causative pathway in the development of the disorder. In response, the placenta secretes soluble substances into the maternal circulation which are responsible for the symptomatic phase of the disease. Among the most well characterized factors in the disease pathology are the anti-angiogenic protein soluble fms-like tyrosine kinase-1 (sFlt-1), inflammatory cytokines, and agonistic angiotensin II type-1 receptor autoantibodies. Each of these factors has been shown to induce hypertension experimentally through the production of endothelin-1 (ET-1), a powerful vasoconstrictor. Antagonism of the endothelin-A receptor has proved beneficial in numerous animal models of gestational hypertension, and it remains an intriguing target for pharmacological intervention in preeclampsia.

Preeclampsia is a pregnancy-induced hypertensive disorder found most commonly in nulliparous women. Recent research performed in animal models of the disease has revealed some of the underlying mechanisms of preeclampsia. Specifically, placental insufficiency and the resulting hypoxia/ischemia have been shown to be crucial to disease progression. In response to placental hypoxia/ischemia, several pathways are activated, which contribute to the clinical manifestations of the disease: increased circulating levels of the anti-angiogenic protein sFlt-1, activation of the maternal inflammatory response, suppressed nitric oxide production, enhanced endothelin-1 production, and induction of reactive oxygen formation. Despite advances in the understanding of the disorder, therapeutic approaches to the treatment of preeclampsia are severely limited. New lines of research, however, indicate some possible new therapeutic approaches for the management of preeclampsia and offer hope for an effective pharmacologic intervention.

Preeclampsia, characterized by new-onset gestational hypertension and proteinuria, is a common and serious complication of pregnancy. Evidence from both animal and human studies has implicated placental ischemia and hypoxia as a central causative factor in the etiology of the disorder. The ischemic placenta in turn initiates a cascade of secondary effector mechanisms, including altered proangiogenic and antiangiogenic factor balance, increase in maternal oxidative stress and endothelial and immunological dysfunction. The full elucidation of these mechanisms will hopefully lead to a more complete understanding of the etiology of preeclampsia and lead to successful therapeutic intervention through the targeted disruption of new and novel pathways.

Pre-eclampsia is a hypertensive disorder of pregnancy initiated by placental insufficiency and chronic ischemia. In response, several pathways activated in the placenta are responsible for the maternal syndrome, including increased production of the anti-angiogenic protein, sFlt-1, and inflammatory cytokines, especially tumor necrosis factor-alpha (TNF-α). Previous studies have demonstrated that heme oxygenase (HO) induction can block TNF-α pathways in vitro and attenuate placental ischemia-induced sFlt-1 in vivo. Here, we investigated whether HO-1 induction could attenuate TNF-α-induced hypertension in pregnant rats. In response to TNF-α infusion (100 ng/day i.p.), maternal mean arterial pressure (MAP) increased vs. control animals (104 ± 3 vs. 119 ± 3 mmHg). HO-1 induction had no effect in control animals, but significantly decreased MAP in TNF-α-infused animals (108 ± 2 mmHg). Placental vascular endothelial growth factor (VEGF) was decreased in response to TNF-α infusion (92 ± 4 vs. 76 ± 2 pg/mg). Placental sFlt-1 was increased by TNF-α infusion (758 ± 45 vs. 936 ± 46 pg/mg, p < 0.05), which trended to normalization by HO-1 induction (779 ± 98 pg/mg). In contrast, HO-1 induction had no significant effect on placental VEGF in TNF-α-infused animals. Taken together, these data suggest that one of the key mechanisms by which HO exerts cytoprotective actions in the placenta during inflammation due to chronic ischemia is through suppression of sFlt-1. Further work elucidating the bioactive metabolites of HO-1 in innate inflammatory responses to placental ischemia is warranted.

Preeclampsia is a hypertensive disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. While the underlying cause is still an active area of investig...

Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia (PE) have yet to be fully elucidated. PE affects the vasculature of many target maternal organs including the kidney, liver, and brain. Growing evidence supports the concept that the placenta plays a central role in the pathogenesis of PE and that reduced uteroplacental perfusion which develops as a result of abnormal cytotrophoblast invasion of spiral arterioles triggers the cascade of events leading to the maternal disorder. The hypoxic placenta in turn releases a variety of soluble factors which that generate widespread dysfunction of the maternal vascular endothelium. This dysfunction manifests as enhanced formation of factors such as endothelin, reactive oxygen species, and augmented vascular sensitivity to angiotensin II. In addition, PE is also associated with decreased formation of vasodilators such as nitric oxide and prostacyclin. The full elucidation of the molecular and cellular mechanisms involved in various stages of the disease process will hopefully lead to a more complete understanding of the etiology of PE and eventually lead to successful therapeutic intervention through the targeted disruption of novel pathways.

Evaluation of: Woods AK, Hoffmann DS, Weydert CJ et al. Adenoviral delivery of VEGF121 early in pregnancy prevents spontaneous development of preeclampsia in BPH/5 mice. Hypertension 57(1), 94–102 (2011).Preeclampsia is a pregnancy-specific hypertension characterized by proteinuria and maternal endothelial dysfunction. Recent research has focused on the balance of pro- and anti-angiogenic factors in the development of the disorder, specifically the proteins VEGF, PlGF, sFlt-1 and sEng. In a recent paper, Woods et al. demonstrated that administration of adenovirally delivered VEGF attenuates the pathological features of preeclampsia that are present in a novel murine model of the disorder, the BPH/5 mouse. This is a recent addition to a body of literature that suggests an important role for VEGF bioavailability in the maintenance of a healthy endothelium during pregnancy, and suggests an intriguing target for the development of new therapeutics for the treatment of preeclampsia.

The last several decades have seen intensive research into the molecular mechanisms underlying the symptoms of preeclampsia. While the underlying cause of preeclampsia is believed to be defective placental development and resulting placental ischemia, it is only recently that the links between the ischemic placenta and maternal symptomatic manifestation have been elucidated. Several different pathways have been implicated in the development of the disorder; most notably production of the anti-angiogenic protein sFlt-1, induction of auto-immunity and inflammation, and production of reactive oxygen species. While the molecular mechanisms are becoming clearer, translating that knowledge into effective therapeutics has proven elusive. Here we describe a number of peptide based therapies we have developed to target theses pathways, and which are currently being tested in preclinical models. These therapeutics are based on a synthetic polymeric carrier elastin-like polypeptide (ELP), which can be synthesized in various sequences and sizes to stabilize the therapeutic peptide and avoid crossing the placental interface. This prevents fetal exposure and potential developmental effects. The therapeutics designed will target known pathogenic pathways, and the ELP carrier could prove to be a versatile delivery system for administration of a variety of therapeutics during pregnancy.

Preeclampsia is a serious complication of pregnancy marked by hypertension and maternal endothelial dysfunction. Recently we have published a series of studies demonstrating that induction of heme oxygenase-1 (HO-1) could attenuate many of the maternal symptoms of preeclampsia in a rodent model of placental ischemia induced by Reductions on Uterine Perfusion Pressure (RUPP). We have further shown that the individual metabolites of HO-1, namely CO and bilirubin, both downregulate hypoxia-induced production of known placental derived pathogenic factors ex vivo. Here, we tested whether , administration of the CO-releasing molecule CORM-3 could attenuate the maternal symptoms of placental ischemia. In response to placental ischemia, rats exhibited marked increases in blood pressure compared to control animals (107 ± 1 vs 136 ± 2mmHg, p

Preeclampsia, a pregnancy specific disorder, is typically defined as new-onset hypertension presenting after the 20th week of gestation with proteinuria. The overall prevalence in the United States is 3% to 8% with higher incidence in specific ethnic subpopulations, notably blacks. Preeclampsia is a major source of maternal and neonatal morbidity and mortality. Moreover, women who endure preeclampsia are at greater risk of cardiovascular diseases later in life. Studies published in Hypertension and other journals during the last few years have provided new insights not only into potential mechanisms underlying the pathophysiology of preeclampsia but also into the identification of potential biomarkers for the early diagnosis of preeclampsia. Although numerous factors have been implicated in the pathophysiology of preeclampsia, the main focus of this Recent Advances article is to review recent studies that link placental ischemia, endothelial and vascular dysfunction, and hypertension in preeclampsia. Despite intense research into the identification of molecular markers of preeclampsia, a reliable and accurate marker for the early diagnosis of preeclampsia remains elusive. A number of recent articles have suggested markers that could prove useful in the diagnosis of the disorder. With the growing interest in autoimmunity in preeclampsia, several studies have looked at immune factors in the maternal circulation as possible biomarkers. For instance, Siddiqui et al1 found widespread (≈95%) presence of agonistic autoantibodies to the angiotensin type-1 receptor (AT1-AA). Additionally, the levels of these autoantibodies correlated well with the degree of disease severity, suggesting potential use in diagnosis. In a related study, Jensen et al2 found that CD19(+)CD5(+) B-cell populations, a potential source for the AT1-AA, are significantly elevated in the maternal circulation of patients with preeclampsia during late gestation when compared with normal-pregnant controls at the same gestational stage. One of the most active areas of research in preeclampsia is angiogenic …

Despite major advances in understanding the pathophysiology of hypertension and availability of effective and safe antihypertensive drugs, suboptimal blood pressure (BP) control is still the most important risk factor for cardiovascular mortality and is globally responsible for more than 7 million deaths annually. Short-term and long-term BP regulation involve the integrated actions of multiple cardiovascular, renal, neural, endocrine, and local tissue control systems. Clinical and experimental observations strongly support a central role for the kidneys in the long-term regulation of BP, and abnormal renal-pressure natriuresis is present in all forms of chronic hypertension. Impaired renal-pressure natriuresis and chronic hypertension can be caused by intrarenal or extrarenal factors that reduce glomerular filtration rate or increase renal tubular reabsorption of salt and water; these factors include excessive activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, increased formation of reactive oxygen species, endothelin, and inflammatory cytokines, or decreased synthesis of nitric oxide and various natriuretic factors. In human primary (essential) hypertension, the precise causes of impaired renal function are not completely understood, although excessive weight gain and dietary factors appear to play a major role since hypertension is rare in nonobese hunter-gathers living in nonindustrialized societies. Recent advances in genetics offer opportunities to discover gene-environment interactions that may also contribute to hypertension, although success thus far has been limited mainly to identification of rare monogenic forms of hypertension.

Maintenance of blood pressure and vascular function during pregnancy is dependent on a carefully orchestrated program of placental development that adequately supplies the developing uteroplacental unit with blood.1 Failure to adequately remodel the uterine vasculature can lead to chronic placental ischemia, now recognized as a central causative agent in several pregnancy pathologies, most notably preeclampsia.2 In recent years, research from numerous labs has identified a number of pathogenic agents produced by the placenta in response to placental ischemia—the VEGF antagonist soluble fms-like tyrosine kinase-1 (sFlt-1) and oxidative stress being major activated targets.3–7 However, even under nonpathological conditions, the placenta is a remarkably hypoxic organ, and it is not entirely clear what intrinsic pathways are responsible for keeping these potentially pathogenic agents in check. There is emerging evidence, however, that these 2 factors can be negatively regulated by the heme oxygenase (HO) system.8,9 HO is commonly considered a housekeeping protein responsible for the degradation of heme released from the breakdown of heme-containing proteins. Heme, a powerful pro-oxidant, is converted by HO into biliverdin, releasing the bioactive molecule carbon monoxide (CO) in the process. Biliverdin is then rapidly converted to bilirubin by biliverdin reductase, and both biliverdin and bililrubin have been shown to have potent antioxidant properties.10,11 HO, and particularly the inducible isoform HO-1, has recently become a target of interest in several pathological states, perhaps most notably hypertension. HO-1 or its metabolites have demonstrated beneficial effects in the treatment of many forms of experimental hypertension, including AngII-dependent, pulmonary, and renovascular hypertension.12–14 Manipulation of the HO-1 system as a therapeutic remains an active area of research. sFlt-1 is perhaps the best-characterized factor released by the ischemic placenta and is a soluble form of the VEGF receptor Flt-1. In the soluble form, sFlt-1 binds free VEGF and makes it unavailable for normal signaling, thereby acting as a potent VEGF antagonist.15 Interestingly, sFlt-1 is also produced at significantly elevated levels by the placenta during even healthy pregnancies, but this is balanced out by a concomitant increase in the VEGF family member placental growth factor (PlGF).16 Preeclampsia then is the imbalanced increase in sFlt-1 in proportion to VEGF/PlGF, but what keeps these factors in balance during normal gestation remains obscure. Intriguingly, several recent reports have demonstrated that HO-1, CO, and bilirubin could negatively affect sFlt-1 production in response to various stimuli.8,9 Oxidative stress has also been intensively studied as a cause of hypertension in response to placental ischemia. Preeclamptic placentas exhibit significant elevations in oxidative stress, and in experimental placental ischemia–induced and sFlt-1–induced hypertension, inhibition of reactive oxygen leads to significant attenuation of the associated hypertension.3,17 Given the hypoxic nature of the healthy placenta, it is not clear how the organ keeps oxidative stress under control. Several recent reports have demonstrated that HO-1 is important for placental development. Crossing of heterozygous HO-1+/- animals leads to significant defects in placental vascular development and structure and placental morphology. This is associated with prevalent fetal demise of the homozygous offspring, lowered fetal weight, decreased litter size, and altered vascular structure and placental morphology regardless of fetal genotype.18,19 However the effects of HO-1 disruption on blood pressure regulation, angiogenic balance, and oxidative stress in late gestation have not been examined. In this study, we have investigated the effect of pharmacological HO inhibition on blood pressure, angiogenic balance, and oxidative stress in late gestation. We demonstrate that HO inhibition leads to an antiangiogenic shift in the placenta, increased placental oxidative stress, and subsequently increased maternal blood pressure.

Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of pre-eclampsia have yet to be fully elucidated. However, it is evident that this is a complex disorder involving multiple organ systems, and by using integrative approaches, enormous progress has been made towards understanding the pathophysiology of pre-eclampsia. Growing evidence supports the concept that the placenta plays a central role in the pathogenesis of pre-eclampsia and that reduced uteroplacental perfusion, which develops as a result of abnormal cytotrophoblast invasion of spiral arterioles, triggers the cascade of events leading to the maternal disorder. Placental ischaemia leads to release of soluble placental factors, many of which are classified as anti-angiogenic or pro-inflammatory. Once these ischaemic placental factors reach the maternal circulation, they cause widespread activation and dysfunction of the maternal vascular endothelium that results in enhanced formation of endothelin-1 and superoxide, increased vascular sensitivity to angiotensin II and decreased formation of vasodilators such as nitric oxide. This review highlights these links between placental ischaemia, maternal endothelial activation and renal dysfunction in the pathogenesis of hypertension in pre-eclampsia.

Preeclampsia is a complication of pregnancy which is marked by hypertension, proteinuria, and maternal endothelial dysfunction. A central factor in the etiology of the disease is the development of...

Preeclampsia is a leading cause of maternal and fetal morbidity during pregnancy, affecting ~5–10% of all pregnancies. Classical hallmarks of the disorder include de novo hypertension, proteinuria, and marked edema, and at present the only effective treatment for the disorder is early delivery of the fetus. In normal gestation, the mother experiences increased cardiac output and fluid volume, while total vascular resistance, renal vascular resistance, vascular reactivity, and arterial pressure show marked decreases. This is in contrast to preeclampsia, in which vascular resistance, pressor response to vasoconstrictors, and arterial pressure are all increased. Recent evidence suggests that these hemodynamic changes are secondary to factors released from the placenta in response to hypoxia and ischemia seen during preeclampsia. This chapter highlights the mechanisms involved and discusses the effects of placental ischemia on the vasculature of the preeclamptic patient.

One potential mechanism contributing to the increased risk for encephalopathies in women with preeclampsia is altered cerebral vascular autoregulation resulting from impaired myogenic tone. Whether placental ischemia, a commonly proposed initiator of preeclampsia, alters cerebral vascular function is unknown. This study tested the hypothesis that placental ischemia in pregnant rats (caused by reduced uterine perfusion pressure [RUPP]) leads to impaired myogenic responses in middle cerebral arteries. Mean arterial pressure was increased by RUPP (135±3 mm Hg) compared with normal pregnant rats (103±2 mm Hg) and nonpregnant controls (116±1 mm Hg). Middle cerebral arteries from rats euthanized on gestation day 19 were assessed in a pressure arteriograph under active (+Ca 2+ ) and passive (0 Ca 2+ ) conditions, whereas luminal pressure was varied between 25 and 150 mm Hg. The slope of the relationship between tone and pressure in the middle cerebral artery was 0.08±0.01 in control rats and was similar in normal pregnant rats (0.05±0.01). In the RUPP model of placental ischemia, this relationship was markedly reduced (slope=0.01±0.00; P P

Preeclampsia (PE) is one of the leading causes of fetal and maternal morbidity, affecting 5–10% of all pregnancies, and lacks an effective treatment. The exact etiology of the disorder is unclear, but placental ischemia has been shown to be a central causative agent. In response to placental ischemia, the antiangiogenic protein fms-like tyrosine kinase-1 (sFlt-1), a VEGF antagonist, and reactive oxygen species are secreted, leading to the maternal syndrome. One promising therapeutic approach to treat PE is through manipulation of the heme oxygenase-1 (HO-1) protein. It has been previously reported that HO-1 and carbon monoxide downregulate sFlt-1 production in vitro, and we have recently shown that HO-1 induction significantly attenuates placental ischemia-induced hypertension, partially through normalization of the sFlt-1-to-VEGF ratio in the placenta. The purpose of this study was to determine whether HO-1 induction would have beneficial effects independently of sFlt-1 suppression. To that end, pregnant rats were continuously infused with recombinant sFlt-1 from gestational days 14–19, and circulating sFlt-1 increased approximately twofold, similar to rats with experimentally induced placental ischemia. In response, mean arterial pressure increased 17 mmHg, which was completely normalized by HO-1 induction. Unbound circulating VEGF was decreased ∼17% in response to sFlt-1 infusion but was increased ∼50% in response to HO-1 induction. Finally, endothelial function was improved as measured by reductions in vascular expression of preproendothelin mRNA. In conclusion, manipulation of HO-1 presents an intriguing therapeutic approach to the treatment of PE.

Although it is well established that the renal endothelin (ET-1) system plays an important role in regulating sodium excretion and blood pressure through activation of renal medullary ETBreceptors, the role of this system in Dahl salt-sensitive (DS) hypertension is unclear. The purpose of this study was to determine whether the DS rat has abnormalities in the renal medullary endothelin system when maintained on a high sodium intake. The data indicate that Dahl salt-resistant rats (DR) on a high-salt diet had a six-fold higher urinary endothelin excretion than in the DR rats with low Na+intake (17.8 ± 4 pg/day vs. 112 ± 44 pg/day). In sharp contrast, urinary endothelin levels increased only twofold in DS rats in response to a high Na+intake (13 ± 2 pg/day vs. 29.8 ± 5.5 pg/day). Medullary endothelin concentration in DS rats on a high-Na+diet was also significantly lower than DR rats on a high-Na+diet (31 ± 2.8 pg/mg vs. 70.9 ± 5 pg/mg). Furthermore, DS rats had a significant reduction in medullary ETBreceptor expression compared with DR rats while on a high-Na+diet. Finally, chronic infusion of ET-1 directly into the renal medulla blunted Dahl salt-sensitive hypertension. These data indicate that a decrease in medullary production of ET-1 in the DS rat could play an important role in the development of salt-sensitive hypertension observed in the DS rat.

Objective We sought to determine the effect of an endothelin type A receptor antagonist (ETA) on uterine artery resistive index (UARI) and mean arterial pressure (MAP) in a placental ischemia rat model of preeclampsia produced by reduction in uterine perfusion pressure (RUPP). Study Design UARI was assessed by Doppler velocimetry in RUPP and normal pregnant controls (NP) on gestational days (GD) 12, 15, and 18. UARI was also determined on GD 18 in NP and RUPP pregnant dams after pretreatment with ETA. MAP was recorded on GD 19. Results The RUPP group had a higher MAP and UARI on GD 15 and 18 than the NP group. Pretreatment with ETA attenuated both the MAP and GD-18 UARI in the RUPP group without affecting these parameters in the NP group. Conclusion The improvement in UARI could be one potential mechanism for the reduction in MAP in response to ETA in pregnant dams with ischemic placentas.