Animal models of preeclampsia: investigating pathophysiology and therapeutic targets.

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.

Syncytialization alters the extracellular matrix and barrier function of placental trophoblasts.

The human placenta is of vital importance for proper nutrient and waste exchange, immune regulation, and overall fetal health and growth. Specifically, the extracellular matrix (ECM) of placental syncytiotrophoblasts, which extends outward from the placental chorionic villi into maternal blood, acts on a molecular level to regulate and maintain this barrier. Importantly, placental barrier dysfunction has been linked to diseases of pregnancy such as preeclampsia and intrauterine growth restriction. To help facilitate our understanding of the interface and develop therapeutics to repair or prevent dysfunction of the placental barrier, in vitro models of the placental ECM would be of great value. In this study, we aimed to characterize the ECM of an in vitro model of the placental barrier using syncytialized BeWo choriocarcinoma cells. Syncytialization caused a marked change in syndecans, integral proteoglycans of the ECM, which matched observations of in vivo placental ECM. Syndecan-1 expression increased greatly and predominated the other variants. Barrier function of the ECM, as measured by electric cell-substrate impedance sensing (ECIS), increased significantly during and after syncytialization, whereas the ability of THP-1 monocytes to adhere to syncytialized BeWos was greatly reduced compared with nonsyncytialized controls. Furthermore, ECIS measurements indicated that ECM degradation with matrix metalloproteinase-9 (MMP-9), but not heparanase, decreased barrier function. This decrease in ECIS-measured barrier function was not associated with any changes in THP-1 adherence to syncytialized BeWos treated with heparanase or MMP-9. Thus, syncytialization of BeWos provides a physiologically accurate placental ECM with a barrier function matching that seen in vivo.

The glycocalyx: a central regulator of vascular function.

The endothelial glycocalyx is a specialized extracellular matrix that covers the apical side of vascular endothelial cells, projecting into the lumen of blood vessels. The composition of the glycocalyx has been studied in great detail, and it is known to be composed of a mixture of proteoglycans, glycosaminoglycans, and glycoproteins. Although this structure was once believed to be a passive physical barrier, it is now recognized as a multifunctional and dynamic structure that participates in many vascular processes, including but not limited to vascular permeability, inflammation, thrombosis, mechanotransduction, and cytokine signaling. Because of its participation in many physiological and pathophysiological states, comprehensive knowledge of the glycocalyx will aid future vascular biologists in their research. With that in mind, this review discusses the biochemical structure of the glycocalyx and its function in many vascular physiological processes. We also briefly review a more recent discovery in glycocalyx biology, the placental glycocalyx.

Immunological comparison of pregnant Dahl salt-sensitive and Sprague-Dawley rats commonly used to model characteristics 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-É£+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.

Therapeutic angiogenesis by vascular endothelial growth factor supplementation for treatment of renal disease.

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.

Preeclampsia and the brain: neural control of cardiovascular changes during pregnancy and neurological outcomes of 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.

Ouabain inhibits placental sFlt1 production by repressing HSP27-dependent HIF-1α pathway.

Up-regulation of placental soluble fms-like tyrosine kinase 1 (sFlt1) contributes to the pathogenesis of preeclampsia. To evaluate novel upstream pathways that regulate placental sFlt1 production, we screened a library of natural compounds (n=502) in human placental cell lines. Here, we report 3 compounds in the cardiac glycoside family, ouabain, gitoxigenin, and digitoxin, that inhibit placental sFlt1 production at nanomolar concentrations in vitro. We further characterized ouabain and demonstrated that it inhibits sFlt1 mRNA and protein expression in human placental cytotrophoblasts and explant cultures in a dose- and time-dependent manner. Ouabain down-regulated sFlt1 production by inhibiting hypoxia-inducible factor 1 (HIF-1α) protein expression in the placenta. Furthermore, we found that phosphorylation of heat-shock protein 27 (HSP27) was necessary for ouabain to inhibit HIF-1α translation. In a rat model of pregnancy-induced hypertension, ouabain reduced mean arterial pressure and enhanced placental HSP27 phosphorylation without any adverse effects on pups. Further studies are needed to explore the usefulness of targeting HIF-1α/HSP27 pathway in preeclampsia.

Placental ischemia induces changes in gene expression in chorionic tissue.

Preeclampsia is a serious and common hypertensive complication of pregnancy, affecting ~5 to 8 % of pregnancies. The underlying cause of preeclampsia is believed to be placental ischemia, which causes secretion of pathogenic factors into the maternal circulation. While a number of these factors have been identified, it is likely that others remain to be elucidated. Here, we have utilized a relevant preclinical rodent model of placental ischemia-induced hypertension, the reduced uterine perfusion pressure (RUPP) model, to determine the effect of chronic placental ischemia on the underlying chorionic tissue and placental villi. Tissue from control and RUPP rats were isolated on gestational day 19 and mRNA from these tissues was subjected to microarray analysis to determine differential gene expression. At a statistical cutoff of p < 0.05, some 2,557 genes were differentially regulated between the two groups. Interestingly, only a small subset (22) of these genes exhibited changes of greater than 50 % versus control, a large proportion of which were subsequently confirmed using qRT-PCR analysis. Network analysis indicated a strong effect on inflammatory pathways, including those involving NF-κB and inflammatory cytokines. Of the most differentially expressed genes, the predominant gene classes were extracellular remodeling proteins, pro-inflammatory proteins, and a coordinated upregulation of the prolactin genes. The functional implications of these novel factors are discussed.

The heme oxygenases: important regulators of pregnancy and preeclampsia.

The heme oxygenase system has long been believed to act largely as a housekeeping unit, converting prooxidant free heme from heme protein degradation into the benign bilirubin for conjugation and safe excretion. In recent decades, however, heme oxygenases have emerged as important regulators of cardiovascular function, largely through the production of their biologically active metabolites: carbon monoxide, bilirubin, and elemental iron. Even more recently, a number of separate lines of evidence have demonstrated an important role for the heme oxygenases in the establishment and maintenance of pregnancy. Early preclinical and clinical studies have associated defects in the heme oxygenase with the obstetrical complication preeclampsia, as well as failure to establish adequate placental blood flow, an underlying mechanism of the disorder. Several recent preclinical studies have suggested, however, that the heme oxygenase system could serve as a valuable therapeutic tool for the management of preeclampsia, which currently has few pharmacological options. This review will summarize the role of heme oxygenases in pregnancy and highlight their potential in advancing the management of patients with preeclampsia.

Heme oxygenase-1 promotes migration and ß-epithelial Na+ channel expression in cytotrophoblasts and ischemic placentas.

Preeclampsia is thought to arise from inadequate cytotrophoblast migration and invasion of the maternal spiral arteries, resulting in placental ischemia and hypertension. Evidence suggests that altered expression of epithelial Na(+) channel (ENaC) proteins may be a contributing mechanism for impaired cytotrophoblast migration. ENaC activity is required for normal cytotrophoblast migration. Moreover, ß-ENaC, the most robustly expressed placental ENaC message, is reduced in placentas from preeclamptic women. We recently demonstrated that heme oxygenase-1 (HO-1) protects against hypertension in a rat model of placental ischemia; however, whether HO-1 regulation of ß-ENaC contributes to the beneficial effects of HO-1 is unknown. The purpose of this study was to determine whether ß-ENaC mediates cytotrophoblast migration and whether HO-1 enhances ENaC-mediated migration. We showed that placental ischemia, induced by reducing uterine perfusion suppressed, and HO-1 induction restored, ß-ENaC expression in ischemic placentas. Using an in vitro model, we found that HO-1 induction, using cobalt protoporphyrin, stimulates cytotrophoblast ß-ENaC expression by 1.5- and 1.8-fold (10 and 50 µM). We then showed that silencing of ß-ENaC in cultured cytotrophoblasts (BeWo cells), by expression of dominant-negative constructs, reduced migration to 56 ± 13% (P < 0.05) of control. Importantly, HO-1 induction enhanced migration (43 ± 5% of control, P < 0.05), but the enhanced migratory response was entirely blocked by ENaC inhibition with amiloride (10 µM). Taken together, our results suggest that ß-ENaC mediates cytotrophoblast migration and increasing ß-ENaC expression by HO-1 induction enhances migration. HO-1 regulation of cytotrophoblast ß-ENaC expression and migration may be a potential therapeutic target in preeclamptic patients.

Heme oxygenase in pregnancy and preeclampsia.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Sildenafil attenuates placental ischemia-induced hypertension.

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/ß-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.

Endothelin as a final common pathway in the pathophysiology of preeclampsia: therapeutic implications.

PURPOSE OF REVIEW: Preeclampsia remains a major health concern in the United States and worldwide. Recent research has begun to shed light on the underlying mechanisms responsible for the symptoms of preeclampsia, and may provide new avenues for therapy for the preeclamptic patient. RECENT FINDINGS: The central role of placental ischemia in the manifestation of preeclampsia has provided new understanding for the origin of pathogenic factors in the preeclamptic patient. The release of soluble factors into the maternal bloodstream from the ischemic placenta is now recognized as a central mechanism in disease manifestation. Specifically, the importance of the vascular endothelial growth factor antagonist soluble fms-like tyrosine kinase and immune factors as factors regulating maternal endothelial dysfunction has become widely acknowledged. Furthermore, mounting evidence implicates the signaling protein endothelin-1 as the final converging factor in the multifaceted cascades that are responsible for the symptomatic manifestation of preeclampsia. Endothelin-1, as a final common pathway in the pathogenic cascade of preeclampsia, presents an intriguing new therapeutic approach for preeclamptic patients. SUMMARY: Identification of antiangiogenic, autoimmune, and inflammatory factors produced in response to placental ischemia have provided potential new avenues for future research into novel therapies for the preeclamptic patient, and suggest new therapeutic avenues for the treatment of preeclampsia.

Induction of heme oxygenase-1 shifts the balance from proinjury to prosurvival in the placentas of pregnant rats with reduced uterine perfusion pressure.

Placental hypoxia/ischemia has been implicated as a central factor in the development of preeclampsia. One particularly useful animal model to study the impact of placental ischemia is the reduced uterine perfusion pressure (RUPP) model. We have previously demonstrated that RUPP animals exhibit elevated placental oxidative stress, which plays an important role in the development of the associated maternal hypertension. Recently, we have demonstrated that cobalt protoporphyrin (CoPP)-mediated induction of heme oxygenase-1 (HO-1) attenuates RUPP-induced oxidative stress and consequent hypertension. However, signaling pathways that are involved in this process are virtually unknown. Here, we show that placentas from RUPP animals exhibit increased phosphorylation of JNK, STAT1, STAT3, and p52shc with a concomitant increase in caspase-3 activation and depletion of intracellular ATP. Treatment with CoPP decreased RUPP-induced phosphorylation of JNK and STAT1, while it increased phosphorylation of ERK and STAT3, leading to decreased caspase-3 activation and restoration of intracellular ATP content. Our data imply that RUPP induces oxidative stress and the consequent injurious state by increasing phosphorylation of mediators of injury (STAT1, JNK) and, to a lesser extent, survival (STAT3, p52shc) in placentas of pregnant rats. HO-1 induction shifts this balance to a prosurvival phenotype by augmenting phosphorylation of the prosurvival ERK and STAT3, while suppressing phosphorylation of JNK and STAT1. This attenuates the resulting injury, as indicated by caspase-3 activation and ATP depletion. These results demonstrate a novel therapeutic activity of HO-1 induction in placental cell survival during ischemia and support the HO-1 pathway as a promising therapeutic target for the management of preeclampsia.

Animal Models of Preeclampsia: Mechanistic Insights and Promising Therapeutics.

Preeclampsia (PE) is a common pregnancy-specific disorder that is a major cause of both maternal and fetal morbidity and mortality. Central to the pathogenesis of PE is the production of antiangiogenic and inflammatory factors by the hypoxic placenta, leading to the downstream manifestations of the disease, including hypertension and end-organ damage. Currently, effective treatments are limited for PE; however, the development of preclinical animal models has helped in the development and evaluation of new therapeutics. In this review, we will summarize some of the more commonly used models of PE and highlight their similarities to the human syndrome, as well as the therapeutics tested in each model.

Nucleosome interaction surface of linker histone H1c is distinct from that of H1(0).

The fully organized structure of the eukaryotic nucleosome remains unsolved, in part due to limited information regarding the binding site of the H1 or linker histone. The central globular domain of H1 is believed to interact with the nucleosome core at or near the dyad and to bind at least two strands of DNA. We utilized site-directed mutagenesis and in vivo photobleaching to identify residues that contribute to the binding of the globular domain of the somatic H1 subtype H1c to the nucleosome. As was previously observed for the H1(0) subtype, the binding residues for H1c are clustered on the surface of one face of the domain. Despite considerable structural conservation between the globular domains of these two subtypes, the locations of the binding sites identified for H1c are distinct from those of H1(0). We suggest that the globular domains of these two linker histone subtypes will bind to the nucleosome with distinct orientations that may contribute to higher order chromatin structure heterogeneity or to differences in dynamic interactions with other DNA or chromatin-binding proteins.

Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats.

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 ET(B) receptors, 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 ET(B) receptor 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.

Induction of heme oxygenase-1 attenuates sFlt-1-induced hypertension in pregnant rats.

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.

Mechanisms and potential therapies for 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.

Elastin-Like Polypeptide: VEGF-B Fusion Protein for Treatment of Preeclampsia.

[Figure: see text].