Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia: Young Investigator Award

doi:10.1016/j.ajog.2004.03.043

American Journal of Obstetrics and Gynecology

Volume 190, Issue 6, June 2004, Pages 1541-1547

https://doi.org/10.1016/j.ajog.2004.03.043 Get rights and content

Abstract

Objective

Soluble vascular endothelial growth factor receptor 1 (sVEGFR-1), which antagonizes VEGF functions, has been implicated in the pathophysiology of preeclampsia. The purpose of this study was to determine whether preeclampsia is associated with a change in the plasma concentration of sVEGFR-1, and, if so, whether such a change is correlated with the severity of the disease.

Methods

A cross-sectional study was conducted to determine the concentrations of sVEGFR-1 in plasma obtained from normal pregnant women (n = 61) and patients with preeclampsia (n = 61). Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay.

Results

Preeclampsia had a higher median plasma concentration of sVEGFR-1 than normal pregnancy (P < .001). The median plasma concentration of sVEGFR-1 was higher in early-onset (≤34 weeks) than late-onset (>34 weeks) preeclampsia (P = .005), and higher in severe than in mild preeclampsia (P = .002). In normal pregnancy, there was a correlation between plasma concentration of sVEGFR-1 and gestational age (r = 0.5; P < .001). In contrast, there was a negative correlation between plasma concentration of sVEGFR-1 and gestational age at the onset of preeclampsia (r = –0.5; P < .001).

Conclusion

Preeclampsia is associated with an increased plasma sVEGFR-1 concentration. The elevation of sVEGFR-1 concentration is correlated with the severity of the disease. These observations suggest the participation of VEGF and its soluble receptor in the pathophysiology of preeclampsia.

Section snippets

Study design

A cross-sectional study was conducted by searching our clinical database and bank of biologic samples. This study included patients with preeclampsia (n = 61) and normal pregnancies (n = 61). Preeclampsia was defined as hypertension (systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg on at least 2 occasions, 4 hours to 1 week apart) and proteinuria (≥300 mg in a 24-hour urine collection or 1 dipstick measurement ≥2+).¹⁴ Patients with preeclampsia were subclassified as either

Results

There were no significant differences in maternal age, maternal weight, body mass index, and gestational age at blood sampling between the 2 groups (Table I). Clinical characteristics of patients with preeclampsia are displayed in Table II. Among preeclamptic patients, 46 (75%) were categorized as having severe preeclampsia. Four patients had a history of chronic hypertension, 1 had renal disease, and none had diabetes before pregnancy.

Patients with preeclampsia had a median plasma

Comment

Our results indicate that women with preeclampsia have a higher plasma concentration of sVEGFR-1 than normal pregnant women. Moreover, the magnitude of the increase was much higher in early-onset or preterm than in late-onset or term preeclampsia. The increased plasma concentration of sVEGFR-1 in preeclampsia was associated with the severity of the disease.

Our findings are consistent with previous studies of Maynard et al¹³ and Koga et al,¹⁵ who found elevated plasma concentrations of sVEGFR-1

References (25)

G.A Dekker et al.
Etiology and pathogenesis of preeclampsia: current concepts
Am J Obstet Gynecol
(1998)
J.M Roberts et al.
Recent Insights into the pathogenesis of pre-eclampsia
Placenta
(2002)
C.W Redman et al.
Preeclampsia: an excessive maternal inflammatory response to pregnancy
Am J Obstet Gynecol
(1999)
M.T Gervasi et al.
Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia
Am J Obstet Gynecol
(2001)
H.P Gerber et al.
Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway: requirement for Flk-1/KDR activation
J Biol Chem
(1998)
H Sugimoto et al.
Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria
J Biol Chem
(2003)
B.M Sibai et al.
Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group
Am J Obstet Gynecol
(1997)
C Hornig et al.
Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids
Lab Invest
(2000)
P.M Bosio et al.
Maternal plasma vascular endothelial growth factor concentrations in normal and hypertensive pregnancies and their relationship to peripheral vascular resistance
Am J Obstet Gynecol
(2001)
Y Zhou et al.
Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome
Am J Pathol
(2002)

H.P Gerber et al.

Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia

J Biol Chem

(1997)

B.Q Shen et al.

Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway

J Biol Chem

(1999)

Cited by (328)

Pre-eclampsia: Re-visiting pathophysiology, role of immune cells, biomarker identification and recent advances in its management
2024, Journal of Reproductive Immunology
Pre-eclampsia (PE) is a hypertension condition that occurs exclusively during pregnancy and has the potential to impact nearly all organ systems. It is estimated to complicate approximately 2–8% of pregnancies worldwide. PE is a prominent medical disorder that poses a significant risk to pregnant mothers and their infants. This review commences by giving the most up-to- date concepts about the pathophysiology of PE. The condition involves atypical infiltration of trophoblast cells into the spiral arteries of the decidua and myometrium, resulting in an insufficient establishment of proper blood flow between the uterus and placenta. The aberrant activation of natural killer (NK) cells in both the peripheral blood and the decidua has been identified as one of the contributing factors to the development of PE. The strong evidence for the genetic etiology of PE is provided by the association between maternal killer cell immunoglobulin-like receptor (KIR) and Human Leukocyte Antigen (HLA-C) in trophoblast cells. Recent observations provide evidence that changes in the expression of anti-angiogenic factors in the placenta are the underlying cause of the clinical symptoms associated with the condition. This review also provides a comprehensive overview of the latest advancements in understanding the underlying causes of PE. It specifically highlights the emergence of new diagnostic biomarkers and their potential implications for therapeutic interventions in managing this medical condition.
Preeclampsia at term: evidence of disease heterogeneity based on the profile of circulating cytokines and angiogenic factors
2024, American Journal of Obstetrics and Gynecology
Intravascular inflammation and an antiangiogenic state have been implicated in the pathophysiology of preeclampsia. On the basis of the profiles of their angiogenic/antiangiogenic factors, women with preeclampsia at term may be classified into 2 subgroups with different characteristics and prevalence of adverse outcomes. This study was undertaken to examine whether these 2 subgroups of preeclampsia at term also show differences in their profiles of intravascular inflammation.
This study aimed to determine the plasma profiles of cytokines and chemokines in women with preeclampsia at term who had a normal or an abnormal angiogenic profile.
A nested case–control study was conducted to include women classified into 3 groups: women with an uncomplicated pregnancy (n=213) and women with preeclampsia at term with a normal (n=55) or an abnormal (n=41) angiogenic profile. An abnormal angiogenic profile was defined as a plasma ratio of placental growth factor and soluble fms-like tyrosine kinase-1 multiple of the median <10th percentile for gestational age. Concentrations of cytokines were measured by multiplex immunoassays.
Women with preeclampsia at term and an abnormal angiogenic profile showed evidence of the greatest intravascular inflammation among the study groups. These women had higher plasma concentrations of 5 cytokines (interleukin-6, interleukin-8, interleukin-12/interleukin-23p40, interleukin-15, and interleukin-16) and 7 chemokines (eotaxin, eotaxin-3, interferon-γ inducible protein-10, monocyte chemotactic protein-4, macrophage inflammatory protein-1β, macrophage-derived chemokine, and thymus and activation-regulated chemokine compared to women with an uncomplicated pregnancy. By contrast, women with preeclampsia at term and a normal angiogenic profile, compared to women with an uncomplicated pregnancy, had only a higher plasma concentration of monocyte chemotactic protein-4. A correlation between severity of the antiangiogenic state, blood pressure, and plasma concentrations of a subset of cytokines was observed.
Term preeclampsia can be classified into 2 clusters. One is characterized by an antiangiogenic state coupled with an excessive inflammatory process, whereas the other has neither of these features. These findings further support the heterogeneity of preeclampsia at term and may explain the distinct clinical outcomes.
Accuracy of placental growth factor alone or in combination with soluble fms-like tyrosine kinase-1 or maternal factors in detecting preeclampsia in asymptomatic women in the second and third trimesters: a systematic review and meta-analysis
2023, American Journal of Obstetrics and Gynecology
This study aimed to: (1) identify all relevant studies reporting on the diagnostic accuracy of maternal circulating placental growth factor) alone or as a ratio with soluble fms-like tyrosine kinase-1), and of placental growth factor-based models (placental growth factor combined with maternal factors±other biomarkers) in the second or third trimester to predict subsequent development of preeclampsia in asymptomatic women; (2) estimate a hierarchical summary receiver-operating characteristic curve for studies reporting on the same test but different thresholds, gestational ages, and populations; and (3) select the best method to screen for preeclampsia in asymptomatic women during the second and third trimester of pregnancy by comparing the diagnostic accuracy of each method.
A systematic search was performed through MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform databases from January 1, 1985 to April 15, 2021.
Studies including asymptomatic singleton pregnant women at >18 weeks’ gestation with risk of developing preeclampsia were evaluated. We included only cohort or cross-sectional test accuracy studies reporting on preeclampsia outcome, allowing tabulation of 2×2 tables, with follow-up available for >85%, and evaluating performance of placental growth factor alone, soluble fms-like tyrosine kinase-1– placental growth factor ratio, or placental growth factor-based models. The study protocol was registered on the International Prospective Register Of Systematic Reviews (CRD 42020162460).
Because of considerable intra- and interstudy heterogeneity, we computed the hierarchical summary receiver-operating characteristic plots and derived diagnostic odds ratios, β, θ_i, and Λ for each method to compare performances. The quality of the included studies was evaluated by the QUADAS-2 tool.
The search identified 2028 citations, from which we selected 474 studies for detailed assessment of the full texts. Finally, 100 published studies met the eligibility criteria for qualitative and 32 for quantitative syntheses. Twenty-three studies reported on performance of placental growth factor testing for the prediction of preeclampsia in the second trimester, including 16 (with 27 entries) that reported on placental growth factor test alone, 9 (with 19 entries) that reported on the soluble fms-like tyrosine kinase-1–placental growth factor ratio, and 6 (16 entries) that reported on placental growth factor-based models. Fourteen studies reported on performance of placental growth factor testing for the prediction of preeclampsia in the third trimester, including 10 (with 18 entries) that reported on placental growth factor test alone, 8 (with 12 entries) that reported on soluble fms-like tyrosine kinase-1–placental growth factor ratio, and 7 (with 12 entries) that reported on placental growth factor-based models. For the second trimester, Placental growth factor-based models achieved the highest diagnostic odds ratio for the prediction of early preeclampsia in the total population compared with placental growth factor alone and soluble fms-like tyrosine kinase-1–placental growth factor ratio (placental growth factor-based models, 63.20; 95% confidence interval, 37.62–106.16 vs soluble fms-like tyrosine kinase-1–placental growth factor ratio, 6.96; 95% confidence interval, 1.76–27.61 vs placental growth factor alone, 5.62; 95% confidence interval, 3.04–10.38); placental growth factor-based models had higher diagnostic odds ratio than placental growth factor alone for the identification of any-onset preeclampsia in the unselected population (28.45; 95% confidence interval, 13.52–59.85 vs 7.09; 95% confidence interval, 3.74–13.41). For the third trimester, Placental growth factor-based models achieved prediction for any-onset preeclampsia that was significantly better than that of placental growth factor alone but similar to that of soluble fms-like tyrosine kinase-1–placental growth factor ratio (placental growth factor-based models, 27.12; 95% confidence interval, 21.67–33.94 vs placental growth factor alone, 10.31; 95% confidence interval, 7.41–14.35 vs soluble fms-like tyrosine kinase-1–placental growth factor ratio, 14.94; 95% confidence interval, 9.42–23.70).
Placental growth factor with maternal factors ± other biomarkers determined in the second trimester achieved the best predictive performance for early preeclampsia in the total population. However, in the third trimester, placental growth factor-based models had predictive performance for any-onset preeclampsia that was better than that of placental growth factor alone but similar to that of soluble fms-like tyrosine kinase-1–placental growth factor ratio. Through this meta-analysis, we have identified a large number of very heterogeneous studies. Therefore, there is an urgent need to develop standardized research using the same models that combine serum placental growth factor with maternal factors ± other biomarkers to accurately predict preeclampsia. Identification of patients at risk might be beneficial for intensive monitoring and timing delivery.
Preeclampsia at term can be classified into 2 clusters with different clinical characteristics and outcomes based on angiogenic biomarkers in maternal blood
2023, American Journal of Obstetrics and Gynecology
An antiangiogenic state has emerged as a mechanism of disease in preeclampsia. Angiogenic biomarkers are used in the risk assessment of this syndrome, particularly of early disease. The role of an antiangiogenic state in late preeclampsia is unclear.
This study aimed to determine the prevalence, characteristics, and clinical significance of angiogenic/antiangiogenic factor abnormalities in women with preeclampsia stratified according to gestational age at delivery.
Two studies were conducted: (1) a longitudinal nested case–control study comprising women with preeclampsia (n=151) and a control group (n=540); and (2) a case series of patients with preeclampsia (n=452). In patients with preeclampsia, blood was collected at the time of diagnosis. Plasma concentrations of placental growth factor and soluble fms-like tyrosine kinase-1 were determined by enzyme-linked immunosorbent assays. An abnormal angiogenic profile was defined as a plasma ratio of placental growth factor and soluble fms-like tyrosine kinase-1 expressed as a multiple of the median <10th percentile for gestational age based on values derived from the longitudinal study. The proportion of patients diagnosed with preeclampsia who had an abnormal angiogenic profile was determined in the case-series participants and stratified by gestational age at delivery into early (≤34 weeks), intermediate (34.1–36.9 weeks), and term (≥37 weeks) preeclampsia. The demographics, clinical characteristics, and pregnancy outcomes of women with preeclampsia with and without an abnormal angiogenic profile were compared.
The prevalence of an abnormal angiogenic profile was higher in preterm than in term preeclampsia (for early, intermediate, and term in the case–control study: 90%, 100%, and 39%; for the case series: 98%, 80%, and 55%, respectively). Women with preeclampsia at term who had an abnormal angiogenic profile were more frequently nulliparous (57% vs 35%), less likely to smoke (14% vs 26%), at greater risk for maternal (14% vs 5%) or neonatal (7% vs 1%) complications, and more often had placental lesions consistent with maternal vascular malperfusion (42% vs 23%; all, P<.05) than those without an abnormal profile. Women with preeclampsia at term who had a normal angiogenic profile had a higher frequency of chronic hypertension (36% vs 21%) and were more likely to have class ≥2 obesity (41% vs 23%) than those with an abnormal profile (both, P<.05).
Patients with early preeclampsia had an abnormal angiogenic profile in virtually all cases, whereas only 50% of women with preeclampsia at term had such abnormalities. The profile of angiogenic biomarkers can be used to classify patients with preeclampsia at term, on the basis of mechanisms of disease, into 2 clusters, which have different demographics, clinical characteristics, and risks of adverse maternal and neonatal outcomes. These findings provide a simple approach to classify preeclampsia at term and have implications for future clinical care and research.
The protective effect of magnesium sulfate on placental inflammation via suppressing the NF-κB pathway in a preeclampsia-like rat model
2023, Pregnancy Hypertension
Abnormal placental inflammation has a role in the pathophysiology of preeclampsia. Magnesium sulfate (MgSO₄) has anti-inflammatory properties and is a fetal neuroprotective agent. MgSO₄ is often used to treat severe preeclampsia; however, the specific mechanisms of action underlying this therapeutic effect remain unclear. The objective of this study was to investigate the effects of MgSO₄ (270 mg/kg) on placental inflammation in a rat model of lipopolysaccharide (LPS; 1.0 µg/kg)-induced preeclampsia. Compared to normal pregnant rats, LPS-treated pregnant rats had higher blood pressure, proteinuria, and expression of the anti-angiogenic factor sFlt-1 and the pro-inflammatory factors interleukin-1β (IL-1β) and IL-12 in placental tissue. LPS-treated pregnant rats had placental insufficiency, poor fetal outcomes, and significantly decreased expression of the anti-inflammatory factors apolipoprotein E (APOE) and IL-10 in placental tissue. MgSO₄ treatment had favorable effects on maternal and fetal outcomes. MgSO₄ treatment improved placental function by repressing an exaggerated inflammatory response in the placenta and promoting angiogenesis via the NF-κB pathway. These findings suggest MgSO₄ has a potential role in the prevention of preeclampsia and in the treatment of mild and moderate preeclampsia.
Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1
2022, Molecular Therapy Nucleic Acids
Preeclampsia (PE) is a rising, potentially lethal complication of pregnancy. PE is driven primarily by the overexpression of placental soluble fms-like tyrosine kinase 1 (sFLT1), a validated diagnostic and prognostic marker of the disease when normalized to placental growth factor (PlGF) levels. Injecting cholesterol-conjugated, fully modified, small interfering RNAs (siRNAs) targeting sFLT1 mRNA into pregnant mice or baboons reduces placental sFLT1 and ameliorates clinical signs of PE, providing a strong foundation for the development of a PE therapeutic. siRNA delivery, potency, and safety are dictated by conjugate chemistry, siRNA duplex structure, and chemical modification pattern. Here, we systematically evaluate these parameters and demonstrate that increasing 2′-O-methyl modifications and 5′ chemical stabilization and using sequence-specific duplex asymmetry and a phosphocholine-docosanoic acid conjugate enhance placental accumulation, silencing efficiency and safety of sFLT1-targeting siRNAs. The optimization strategy here provides a framework for the chemical optimization of siRNAs for PE as well as other targets and clinical indications.

View all citing articles on Scopus

^☆: Presented at the 70th Annual Meeting of the Central Association of Obstetricians and Gynecologists, October 1-4, 2003, LaJolla, Calif. Young Investigator's Award

View full text

Transactions of the 70th annual meeting of the central association of obstetricians and gynecologistsEvidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia: Young Investigator Award☆

Abstract

Objective

Methods

Results

Conclusion

Section snippets

Study design

Results

Comment

Am J Obstet Gynecol

Placenta

Am J Obstet Gynecol

Am J Obstet Gynecol

J Biol Chem

J Biol Chem

Am J Obstet Gynecol

Lab Invest

Am J Obstet Gynecol

Am J Pathol

J Biol Chem

J Biol Chem

Transactions of the 70^th annual meeting of the central association of obstetricians and gynecologists
Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia: Young Investigator Award☆