Review
Angiogenic and antiangiogenic factors in preeclampsia

https://doi.org/10.1016/j.prp.2017.10.021Get rights and content

Highlights

  • The expression of VEGF-A, PlGF, endoglin, Flt-1, Flk-1, sFlt-1 and sEng, is fundamental to the establishment of uteroplacental circulation.

  • There is an increased expression of sFlt-1 and sEng, a decreased expression of VEGF-A and PlGF, and impaired angiogenesis and vasculogenesis.

  • The imbalance between angiogenic and anti-angiogenic factors seems to be triggered by the increased expression of endothelin-1 and TNF-α.

  • It has been possible to establish an efficient and effective diagnostic tool.

Abstract

Background

Pre-eclampsia is a multifactorial hypertensive disorder that is triggered by placental insufficiency and that accounts for up to 15% of maternal deaths. In normal pregnancies, this process depends on the balance between the expression of angiogenic factors and antiangiogenic factors, which are responsible for remodeling the spiral arteries, as well as for neoangiogenesis and fetal development.

Purpose

The aim of this review is to discuss the main scientific findings regarding the role of angiogenic and antiangiogenic factors in the etiopathogenesis of preeclampsia.

Methods

An extensive research was conducted in the Pubmed database in search of scientific manuscripts discussing potential associations between angiogenic and antiangiogenic factors and preeclampsia. Ninety-one papers were included in this review.

Results

There is an increased expression of soluble fms-like tyrosine kinase receptor and soluble endoglin in pre-eclampsia, as well as reduced placental expression of vascular endothelial growth factor and placental growth factor. Systemic hypertension, proteinuria and kidney injury – such as enlargement and glomerular fibrin deposit, capillary occlusion due to edema, and hypertrophy of endocapillary cells – are some of these changes. The complex etiopathogenesis of preeclampsia instigates research of different biomarkers that allow for the early diagnosis of this entity, such as vascular endothelial growth factor, placental growth factor, soluble fms-like tyrosine kinase receptor, soluble endoglin, placental glycoprotein pregnancy-associated plasma protein-A and protein 13.

Conclusion

Even though it is possible to establish an efficient and effective diagnostic tool, three key principles must be observed in the management of preeclampsia: prevention, early screening and treatment.

Introduction

Preeclampsia (PE) is a complex hypertensive pregnancy syndrome that affects between 2 and 7% of pregnant women after the 20th week, and which may appear superimposed on chronic hypertension (CH), for instance. It is characterized by systolic blood pressure  140 mm Hg and/or diastolic blood pressure  90 mm Hg in hypertensive women, followed by proteinuria  300 mg/L in urine/24 h [1], [2], [3]. Moreover, the presence of thrombocytopenia (platelets < 100,000/mμl), renal failure (creatinine  1.1 mg/dl) or impairment of liver function (doubled normal concentration of oxaloacetic transaminase and pyruvate transaminase), pulmonary edema, as well as cerebral and visual disturbances, accompanied by hypertension [4] in the absence of proteinuria, are other criteria for the diagnosis of PE [3], [5].

Eclampsia, from the Greek eklampsis (lightning), refers to the sudden onset of persistent headache, photophobia, scotomas, epigastric pain or pain in the right upper quadrant, as well as seizures [3], [6]. It is noteworthy that the impairment of hepatic and renal function may lead to hemolysis, which is characterized by increased plasma level of lactate dehydrogenase, persistent increase in the level of liver enzymes and in thrombocytopenia, which is called HELLP (hemolysis, elevated liver enzymes and low platelets) [7]; and which may lead to intense inflammatory response, endothelial injury, generalized vascular resistance [8], disseminated intravascular coagulation, hepatic infarction, cerebral vascular disease, premature placental abruption and oliguria [2], [3], for instance.

Different risk factors for PE have been discussed in the literature, and predisposing factors may include the following: African descent, obesity, short stature, nutritional deficiencies, previous CH (prevalent in up to 35% of the cases) or gestational hypertension [9] in previous pregnancies, heredity, urinary tract infections, diabetes mellitus, autoimmune diseases, hydatidiform mole, multiple pregnancy, and fetal macrosomia [10], [11], [12], [13]. According to Chaiworapongsa et al. [15], other factors include primiparity in young women, which is associated with intolerance of the maternal immune system to paternal alloantigens present in the seminal fluid and in the sperm; heredity, represented by the presence of genetic variations in collagen α1-chain (I), interleukin-1α (IL-1α), urokinase-type plasminogen activator receptor; maternal-fetal incompatibility of lymphotoxin-α, von Willebrand factor, and α2 chain of collagen [14]; mutations in factor V Leiden, in human leukocyte antigen, in endothelial nitric oxide synthases, and in angiotensin converting enzyme [15].

Although little is known about the etiopathogenesis of preeclampsia, this syndrome has a major impact on maternal and fetal health worldwide, since it is responsible for 10–15% of maternal deaths [16], [17], preterm births, intrauterine growth restriction (IUGR), and fetal deaths [2]. In developing countries, there are high rates of maternal morbidity and mortality from PE, mainly due to poor prenatal care [16]. In Brazil, according to data by the National Health System (SUS, in Portuguese) [18], approximately 76,000 maternal deaths and 500,000 perinatal deaths are estimated to be associated with PE every year, with an average of three maternal deaths/day due to complications arising from the disease [19].

Therefore, the identification of risk factors and the establishment of criteria for the diagnosis of PE are essential for the effective treatment and prevention of complications during pregnancy. Platelet count, measurement of hepatic enzymes, evaluation of proteinuria and blood pressure levels, weight gain monitoring, analysis of kidney and lung function, and assessment of previous pregnancy history (e.g. premature birth, children born small for gestational age, etc.) must be recorded during prenatal care. However, it is interesting to note that this entity may have atypical manifestations as those observed in the HELLP syndrome, yet in the absence of proteinuria and hypertension; thereby, careful research and analysis of signs and symptoms of pregnant women are required [2], [3].

According to the literature, several mechanisms are associated with the development of this multifactorial syndrome, including changes during placentation [20], oxidative stress [21], [22], exacerbated inflammatory response [23], [24], [25], thrombosis, activation of the renin-angiotensin-aldosterone system [25], [26], and endothelial dysfunction caused by changes in the angiogenic profile [27]; the latter is associated with the pathophysiological changes described in PE.

Section snippets

Etiopathogenesis of preeclampsia

The pathophysiology of PE remains largely unknown. Nonetheless, this hypertensive disorder is thought to be triggered by placental dysfunction, which favors the synthesis of specific factors in the maternal circulation that are responsible for causing clinical changes in PE [2], [28].

In normal pregnancies, cytotrophoblasts (cells outside the blastocyst layer) invade the uterine wall between the 6th and 8th week, destroy the muscular middle layer, acquire endothelial cell phenotype, and

Angiogenic and antiangiogenics factors

The placenta is an organ that is highly vascularized by maternal and fetal blood vessels, and its development, maturation and functions depend on efficient vasculogenesis (de novo formation of new blood vessels), on angiogenesis (the formation of new blood vessels from other pre-existing vessels), and on cytotrophoblast invasion for spiral artery remodeling, which is called pseudo-vasculogenesis [49], [50], [51].

In normal pregnancies, the expression of different molecules, such as integrins,

Biomarkers and management of preeclampsia

The complex etiopathogenesis of PE instigates worldwide research on the definition of clinical and laboratory parameters that allow for the early diagnosis of this entity. Because systemic hypertension and proteinuria are not specific symptoms [5], different biomarkers have been investigated as promising diagnostic tools [69], [87], [88].

In the first and second trimesters of pregnancy, the relationship between sFlt-1/PlGF is regarded as a promising index of the imbalance between angiogenic and

Conclusion

Preeclampsia has a major impact on maternal and fetal health, since it is responsible for up to 15% of maternal deaths. Even though there are different predisposing factors, such as African descent, obesity and previous CH, this hypertensive disorder is believed to be triggered by a change in the expression of angiogenic and anti-angiogenic factors, which appears to be the key factor in the endothelial dysfunction observed in this entity.

The expression of VEGF-A, PlGF, endoglin, and their

Funding

This study was funded by Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq) (grant number 470029/20110), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (grant number PNPD-02604/094), Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (grant number CDS-APQ-02135-14), and Fundação de Ensino e Pesquisa de Uberaba (FUNEPU) (grant number CDS-922/2009). All them from Brazil.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Author contributions

Fernanda Rodrigues Helmo: ‘I declare that I participated in the project development, data collection, manuscript writing/editing and that I have seen and approved the final version. I have no conflicts of interest’. Angela Maria Moed Lopes: ‘I declare that I participated in the project development, data collection, manuscript writing and that I have seen and approved the final version. I have no conflicts of interest’. Anna Cecília Dias Maciel Carneiro: ‘I declare that I participated in the

Acknowledgements

We thank Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), and Fundação de Ensino e Pesquisa de Uberaba (FUNEPU) for financial support.

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