2013

http://informahealthcare.com/jmfISSN: 1476-7058 (print), 1476-4954 (electronic)

J Matern Fetal Neonatal Med, 2013; 26(10): 978–983! 2013 Informa UK Ltd. DOI: 10.3109/14767058.2013.766692

The role of VEGF and its soluble receptor VEGFR-1 in preterm newbornsof preeclamptic mothers with RDS

Salih Kalay1, Burak Cakcak1, Osman Oztekin1, Gonul Tezel1, Ozgur Tosun2, Mustafa Akcakus1, and Nihal Oygur1

1Department of Pediatrics, Akdeniz University Medical School, Antalya, Turkey, and 2Department of Biostatistics, Akdeniz University Medical School,

Antalya, Turkey

Abstract

Objective: We measured vascular endothelial growth factor (VEGF) and soluble VEGF receptor1(sVEGFR-1) concentrations in cord blood and tracheal aspirate fluid (TAF) in order toinvestigate the role of them in lung maturation and the severity of respiratory distresssyndrome (RDS) in preterm newborns, born to preeclamptic mothers.Methods: Newborns were divided into two groups as preterms born to preeclamptic mothersand preterms born to healthy mothers. They were also divided into two groups as severe RDS(sRDS) and mild RDS (mRDS) according to the need of surfactant and extent or type ofventilatory support. The concentrations of VEGF and sVEGFR-1 in cord blood and TAF (only inpreterms with sRDS) were assayed by standardized enzyme-linked immunosorbent assay.Results: When the patients were evaluated as sRDS and mRDS, cord blood VEGF and VEGF/sVEGFR-1 concentrations of preterms with sRDS were significantly lower than the concentra-tions of preterms with mRDS. Conversely, cord blood sVEGFR-1 concentrations of preterms withsRDS were significantly higher than the concentrations of preterms with mRDS. VEGF andsVEGFR-1 concentrations in TAF could be compared only between sRDS preterms, born topreeclampsia (þ) and (�) mothers. No statistical significance was detected between the twogroups when sVEGFR-1, VEGF and VEGF/sVEGFR-1 concentrations in TAF were compared.Conclusion: Preeclampsia seems not to have an important effect on VEGF and sVEGFR-1concentrations of preterm newborns both in cord blood and in TAF. Low VEGF and highsVEGFR-1 concentrations seem to be associated with the severity of RDS irrespective ofpreeclampsia, suggesting that VEGF may be one of the main components of lung maturation.

Keywords

Preeclampsia, preterm newborn, respiratorydistress syndrome, vascular endothelialgrowth factor, vascular endothelial growthfactor receptor 1

History

Received 29 July 2012Revised 1 January 2013Accepted 10 January 2013Published online 13 February 2013

Introduction

Vascular endothelial growth factor (VEGF) is accepted as an

important growth factor in lung maturation. It plays an

essential role not in only embryogenesis, but also in postnatal

vasculogenesis, angiogenesis and development of the alveolar

capillary bed in the lung. It has also been shown that VEGF

stimulates surfactant production by alveolar type II cells

[1–3]. VEGF exerts its biological effects via 2 tyrosine kinase

receptors, VEGF receptor (VEGFR)-1 and VEGFR-2. These

receptors function as endogenous dominant-negative regula-

tors of VEGF, by complexing with VEGF with similar affinity

as the membrane receptor, thereby preventing downstream

signal transduction. Soluble VEGFR-1 is accepted as an

important receptor in VEGF regulation during lung develop-

ment. Studies investigating the role of VEGF and sVEGFR-1

in respiratory distress syndrome (RDS) or chronic lung

disease in newborns have shown that preterms with more

severe RDS (sRDS) have lower cord blood VEGF levels or

preterms which develop bronchopulmonary dysplasia have

low VEFG levels in tracheal aspirate fluid (TAF), concurrent

with elevated sVEGFR-1 levels on the first day of life [4–7].

Preeclampsia is a multisystem disorder of unknown cause

that is unique to human pregnancy. It is characterized by

abnormal vascular response to placentation that is associated

with increased systemic vascular resistance, enhanced platelet

aggregation, activation of the coagulation system and endo-

thelial cell dysfunction [8,9]. VEGF and sVEGFR-1 are also

thought to have important roles in the pathogenesis of

preeclampsia. Due to the results of many studies it has been

accepted that in pregnant women with preeclampsia, the

placenta produces elevated levels of sVEGFR-1, which

captures free VEGF. As a result, the normal vasculature in

the kidney, brain, lungs and other organs of mothers are

deprived of essential survival and maintenance signals and

become dysfunction [10–13]. However, it is not clear whether

VEGF, sVEGFR-1 levels and the lung maturation of

newborns, born to preeclamptic mothers are also different

from babies, born to healthy mothers.

Several studies have shown a reduced risk of RDS or

earlier lung maturation in infants who were born to patients

with preeclampsia and hypertension [14–16]. In contrast,

more recently, a few studies have failed to demonstrate any

protective effect of preeclampsia in the development of RDS

Address for correspondence: Dr Nihal Oygur, Department of Pediatrics,Division of Neonatology, Akdeniz University Faculty of Medicine,Antalya, Turkey. E-mail: nihaloygur@akdeniz.edu.tr

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by acceleration of fetal lung maturation [17,18]. However,

these studies are only based on the incidence of RDS in the

newborns of hypertensive mothers.

Studies, investigating the role of VEGF and its soluble

receptor in lung maturation were only about preterms with

RDS, irrespective of maternal preeclampsia [4–6]. Besides,

some studies compared the cord blood VEGF and sVEGFR-1

concentrations of babies born to preeclamptic and healthy

mothers irrespective of RDS [19–21]. We could not detect any

study in literature investigating the role of VEGF and

sVEGFR-1 in the development of RDS in preterms of

preeclamptic mothers.

This study was conducted to investigate whether maternal

production of VEGF and sVEGFR-1 (a) can change the

concentration of this growth hormone and its soluble receptor

in cord blood and TAF in preterm newborns of preeclamptic

mothers and (b) can affect lung maturation and the severity of

RDS in these babies.

Methods

This study was performed with the approval of the Ethics

Committee of Akdeniz University Faculty of Medicine.

Informed Consent Form was read and signed by parents or

guardians prior to the study.

Study subjects

This study was conducted at Akdeniz University Medical

School Hospital between February 2010 and April 2012. All

infants born at or before 32þ 0 weeks of gestation either to

preeclamptic or to healthy mothers were recorded during this

period. The preeclamptic pregnants with chorioamnionitis,

infection, chronic hypertension, chronic renal or cardiac

disease, active asthma, thyroid disease and epilepsia were

excluded from the study. Preterms with the evidence of

congenital heart disease, various lung diseases other than

RDS, hypoxic or traumatic birth, malformation of the central

nervous system, IUGR, circulatory failure or kidney abnorm-

alities were also excluded.

Newborns included in the study were divided into two

groups as preterms born to preeclamptic mothers and preterms

born to healthy mothers. They were also divided into two

groups as severe RDS (sRDS) and mild RDS (mRDS)

according to the need of surfactant and extent or type of

ventilatory support.

Gestational age (GA) was estimated by last menstrual date,

New Ballard Score or prenatal ultrasound. Data about

antenatal betamethasone administration was obtained from

patient charts.

Preeclampsia was defined as an increased diastolic blood

pressure (490 mmHg) or increased diastolic blood pressure of

15 mmHg over baseline value, with proteinuria (4300 mg/

24 h) on urine analysis [22]. Healthy pregnant was defined as

normotensive, non-proteinuric, pregnant women with no

medical or obstetric complications.

RDS was defined as acute respiratory failure in the first

postnatal hours with characteristic chest radiograph changes

in the absence of sepsis, pneumonia, or other causes of

respiratory distress. Preterms with severe nasal flaring,

grunting, tachypnea, retractions, cyanosis and with severe

pulmonary opacification that obscurated the cardiac and

diaphragmatic margins and with also prominent air brocho-

grams on chest radiography, were accepted as sRDS. Preterms

with mild respiratory symptoms and mild reticulogranular

appearance with also limited air bronchograms on chest

radiography were accepted as mRDS. Patients with sRDS

were immediately put on mechanical ventilator and exogen-

ous surfactant was administered within 2 h after birth. Four

patients needed a second dose of surfactant, 8 h after the first

dose. All preterms with sRDS were extubated as soon as

possible and put on CPAP. Preterms with mRDS were directly

put on CPAP and oral caffeine was started.

Data obtained for all infants included: birth weight (BW),

GA, mode of delivery, sex, antenatal use of corticosteroid,

Apgar score at 5 min of life and use of mechanical ventilation.

VEGF and sVEGFR-1 concentrations of plasma samples,

obtained from cord blood and TAF (only sRDS preterms),

were measured with enzyme-linked immunosorbent assay

(ELISA) and the ratios of VEGF to sVEGFR-1 in TAF were

also calculated.

Collection of blood and VEGF, sVEGFR-1 measurement

Umbilical venous cord blood samples were obtained upon

delivery. All the samples were centrifuged within 15 min of

collection. Plasma was kept at �70 �C until analysis by a

technician who was unaware of the patient’s condition. The

concentrations of VEGF and sVEGFR-1 in cord blood were

assayed by ELISA (R&D Systems, Minneapolis, MN) in

duplicate, according to the protocol recommended by the

manufacturer. The lower limit of detection was510 pg/mL.

Tracheal aspiration fluid sample collection

TAF samples were obtained from infants who required

mechanical ventilation by standardized routine tracheal

lavage as previously described [23,24]. TAF samples were

taken within 2 h after birth and before surfactant administra-

tion. Briefly, 1 ml of sterile isotonic saline was instilled into the

endotracheal tube, the patient was manually ventilated for three

breaths, and the trachea was suctioned twice for 5 s. Lavage

fluid was consistent (2–3 ml) in all subjects each time. Tracheal

aspirates were collected into a trap and transferred into tubes

containing 500 IU of aprotinin (Trasylol; Bayer, Leverkusen,

Germany) and 5 mg of deferoxiamine (Desferal; Ciba, Basel,

Switzerland). The tubes were stored at �20 �C until analysis.

The levels of VEGF and sVEGFR-1 in TAF were assayed by a

standardized ELISA (R&D Systems) in duplicate, according to

the protocol recommended by the manufacturer.

Assay for VEGF and soluble receptors in trachealaspirate samples

All of the assays were conducted in duplicate. To determine

the levels of VEGF and sVEGFR-1 in TAF, samples were

assayed using commercial sandwich immunoassay kits (R&D

Systems). All assays were performed according to the

manufacturer’s protocol. VEGF and soluble receptor concen-

trations in the sample were determined from a linear

standard curve ranging from 0 to 2000 pg/mL for VEGF

and sVEGFR-1. The coefficients of variation from interassay

DOI: 10.3109/14767058.2013.766692 VEGF and its soluble receptor VEGFR-1 in preterm newborns 979

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and intra-assay precision assessments were 10% for all of the

assays. To estimate the in situ TAF concentration of VEGF

and sVEGFR-1, a correction for dilution was calculated using

the ratio of urea-N in the tracheal aspirate sample.

Urea assay

Urea concentration in tracheal lavage fluid was quantitatively

assayed with reagents from Sigma Diagnostics (St. Louis,

MO). The concentration of serum urea was measured by the

hospital chemistry laboratory from a blood sample taken for

routine clinical management within 6 h of lavage. Epithelial

lining fluid (ELF) volume was calculated as follows

ELF ¼ TA urea=Serum ureað Þ � TA volume

Concentrations of VEGF and sVEGFR-1 in TA samples

were all normalized to the ELF to correct for dilution during

the sampling procedure.

Statistical analysis

All statistical analyses were performed with Statistical

Package for Social Sciences (SPSS, Version 16.0, Chicago,

IL) software. Data were summarized as median (range).

Shapiro–Wilk test was used to test the normality condition for

distributions of continuous variables. As for univariate

methods, differences between groups were assessed by

either Mann–Whitney U test or Student’s t-test, depending

on their distributions. Group differences in nominal variables

were assessed with Chi-square test.

In order to understand whether VEGF, sVEGFR-1 con-

centrations in cord blood show statistically significant differ-

ence between RDS groups, multivariate General Linear

Model (GLM) was used. Since GA and BW showed

statistically significant associations with VEGF, sVEGFR-1,

GA and BW were assigned as the covariates of GLM model.

Group differences based on VEGF and sVEGFR-1 concen-

trations were then evaluated using GLM, adjusted for

covariates. Statistical significance was assumed for all tests

when p50.05.

Results

Demographic and clinical characteristics of subjects

A total of 180 pregnants delivered preterms of 32þ 0 weeks

or lower gestation during the study period. Out of 180, 42

were preeclamptic. Four of them were excluded from the

study as one had chronic renal disease, two had chronic

hypertension and one had epilepsy. Therefore 37 preeclamptic

pregnant were found eligible for the study. Out of 138 healthy

pregnants, 37 were randomly enrolled in the study.

Out of 37 preterms born to preeclamptic pregnant, five

were excluded from the study due to the different pathologies

as congenital heart disease, various lung diseases other than

RDS, hypoxic or traumatic birth, malformation of the central

nervous system. Parental consent for umbilical cord blood

sample could not be obtained from two preterms. Out of 37

preterms born to healthy pregnants, parental consent could not

also be obtained from 13, for umbilical cord blood sample.

Therefore 54 preterms (preterm infants of 30 preeclamptic and

24 healthy pregnant) were enrolled in this study.

Out of 30 preterms born to preeclamptic mothers, sRDS

developed in nine and mRDS in 21; out of 24 preterms born to

healthy mothers sRDS developed in 10 and mRDS in14.

Demographic and clinical characteristics of the studied

population according to sRDS, mRDS and preeclampsia (þ)

preeclampsia (�) groups were shown in Tables 1 and 2. GA,

BW and Apgar score at 5 min of postnatal life in preterms

with sRDS were significantly lower than in preterms with

mRDS (p: 0.043 for GA; p: 0.036 for BW and p: 0.01 for

Apgar score). GA and BW of preterms born to preeclamptic

mothers were significantly lower than in preterms born to

healthy mothers (p: 0.025 for GA; p: 0.045 for BW). The rate

of caesarean section in mothers with preeclampsia, was higher

than healthy mothers (p: 0.019).

Laboratory results of subjects

VEGF and sVEGFR-1 concentrations were assayed in 54 cord

blood samples. When the patients were evaluated as sRDS

and mRDS, cord blood VEGF concentrations and VEGF/

sVEGFR-1 ratios of preterms with sRDS were significantly

lower than preterms with mRDS (p: 0.001 for VEGF and

p: 0.001 for VEGF/sVEGFR-1). Conversely, cord blood

sVEGFR-1 concentrations of preterms with sRDS were

significantly higher than the sVEGFR-1 concentrations of

preterms with mRDS (p: 0.002) (Table 1 and Figures 1 and 2).

When the patients were evaluated as preeclampsia (þ) and

preeclampsia (�) preterms, cord blood VEGF, sVEGFR-1

concentrations and VEGF/sVEGFR-1 ratios were insignifi-

cant (Table 2).

Table 1. Demographic and clinical characteristics with VEGF and sVEGFR-1 levels of the studied population according to sRDSand mRDS groups.

sRDS (n:19) mRDS (n:35) p**

Gestasyonel age (weeks)* 29 (28–31) 31 (29–32) 0.043BW (g)* 1080 (980–1700) 1590 (1342–1950) 0.036Sex (female/male) 8/11 17/18 0.94Cesarean section 18 29 0.63Apgar score at 5 min* 4 (3–5) 8 (6–8) 0.01Antenatal steroids 17 30 0.18VEGF (pg/ml) (adjusted for GA and BW) 18.5 (8.9–48) 215 (16–1408) 0.001sVEGFR-1 (pg/ml) (adjusted for GA and BW) 643 (135–1395) 206 (86–409) 0.0001VEGF/sVEGFR-1 0.35 (0.01–0.28) 1.46 (0.04–6.08) 0.001

*Median (min–max).**p50.05 as significant.

980 S. Kalay et al. J Matern Fetal Neonatal Med, 2013; 26(10): 978–983

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Figure 2. Cord blood sVEGFR-1 levels ofmRDS and sRDS preterms (adjusted for GAand BW).

Figure 1. Cord blood VEGF levels ofmRDS and sRDS preterms (adjusted for GAand BW).

Table 2. Demographic and clinical characteristics with VEGF and sVEGFR-1 levels of the studied population according topreeclampsia (þ) and preeclampsia(�) groups.

Preeclampsia(þ) (n:30) Preeclampsia(�) (n:24) p**

Gestasyonel age (weeks)* 30 (28–31) 31 (29–32) 0.025BW (g)* 1320 (980–1950) 1480 (850–1800) 0.045Sex (female/male) 14/16 11/13 0.86Cesarean section 28 19 0.019Apgar score at 5 min* 6 (3–8) 6 (3–8) 0.96Antenatal steroids 24 16 0.13sRDS 9 10 0.37VEGF levels (pg/ml)* 42 (12–1408) 69 (9–1274) 0.344sVEGFR-1 levels (pg/ml)* 446 (86–1349) 311 (129–857) 0.355VEGF/sVEGFR-1* 0.19 (0.01–6.08) 0.315 (0.01–5.17) 0.284

*Median (min–max).**p50.05 as significant.

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Due to the ethical problems, TAF samples could be

obtained only from preterms who have been incubated for

mechanical ventilation, so, VEGF and sVEGFR-1 concentra-

tions in TAF could be compared only between sRDS preterms

born to preeclampsia (þ) mothers and sRDS preterms born to

preeclampsia (�) mothers. A total of 19 TAF samples were

collected after birth. However no statistical significance was

detected between the two groups when sVEGFR-1, VEGF and

VEGF/sVEGFR-1 concentrations in TAF were compared

(p: 0.26 for VEGF, p: 0.96 for sVEGFR-1, p: 0.48 for VEGF/

sVEGFR-1) (Table 3).

After adjustments with GA and BW, the differences in

VEGF and sVEGFR-1 levels between RDS groups were

investigated with GLMs. Both concentrations showed statis-

tically significant difference between RDS groups after the

adjustments (for VEGF: p¼ 0.001 and for sVEGFR-1:

p¼ 0.0001) (Table 1).

Discussion

Soluble VEGFR-1 has been proposed as a possible circulating

endothelial damaging factor in preeclampsia. Soluble

VEGFR-1 mRNA is up-regulated in preeclamptic placentas,

possibly due to placental hypoxia. It acts as a potent VEGF

and placental growth factor (PlGF) antagonist by binding

VEGF and PlGF molecules, thereby reducing free-circulating

concentrations of VEGF and PlGF [8–11,13,25–27]. The

rapid decline of sVEGFR-1 concentrations after delivery

found by Maynard et al. [12] supports a placental origin of

sVEGFR-1 in preeclampsia.

Studies investigating VEGF, sVEGFR-1 levels in pre-

eclamptic pregnant and their newborns had conflicting results.

According to the study done by Staff et al. [25] sVEGFR-1

concentration was elevated in fetal circulation in preeclampsia,

but at a much lower level than in the maternal circulation.

Similarly, Schlembach et al. [9], Catarino et al. [19] and Kwon

et al. [20] reported that umbilical venous serum concentrations

of sVEGFR-1 were significantly elevated and VEGF concen-

trations were significantly decreased in preeclampsia, com-

pared to normal pregnancies. Similarly, Tsao et al. [5] found

sVEGFR-1 levels significantly high in the cord blood of

preeclampsia. In contrast, Galazios [21] detected umbilical

cord serum VEGF levels of newborns born to preeclamptic

women significantly higher than in newborns born to healthy

women. In the light of these suggestions, we hypothesized that

the placental secretion of angiogenic factors in preeclampsia

may affect their concentrations, not only in fetal circulation,

but also in the lung. Therefore, we measured cord blood

concentrations of free VEGF and sVEGFR-1 in preterms of

preeclamptic and healthy mothers. We also measured their

concentrations in TAF only in sRDS preterms with and

without preeclamptic mothers.

According to our blood results, there was no significant

difference between the cord blood VEGF and sVEGFR-1

concentrations of preterms with preeclamptic mothers and

preterms with healthy mothers suggesting that preeclampsia

did not influence or play an important role in VEGF and

sVEGFR-1 concentrations of babies, born to preeclamptic

mothers.

RDS due to surfactant deficiency is a common cause of

morbidity and mortality in premature infants. An increasing

evidence suggests that VEGF may contribute to surfactant

secretion and pulmonary maturation [2,28]. VEGF is a

specific endothelial cell mitogen that regulates endothelial

cell differentiation, angiogenesis, and maintenance of existing

vessels [29–31]. VEGF has been shown to be deposited in the

sub epithelial matrix at the leading edges of branching

airways where it stimulates angiogenesis [32]. Additionally,

VEGF induces airway epithelial-cell proliferation in human

lungs in vitro [33]. In human fetal lung, VEGF is localized in

alveolar epithelial cells and myocytes, suggesting a paracrine

role for VEGF in modulating activities in adjacent vascular

endothelium [30]. Compernolle et al. [2] showed that type II

cells respond to VEGF treatment with increased surfactant

protein (SP)-B and SP-C production. In the study by Lassus

et al. [4], infants with sRDS had less VEGF in their TAF

during the early postnatal period than infants with mRDS and

cord blood VEGF elevation was correlated with absence of

RDS. These data suggested that VEGF might be a marker of

pulmonary maturity.

In our study, cord blood VEGF, VEGF/sVEGFR-1 con-

centrations of preterm with sRDS were found significantly

lower (p: 0.001 for both VEGF and VEGF/sVEGFR-1) and

sVEGFR-1 concentrations were found significantly higher

(p: 0.002) than the concentrations of preterms with mRDS.

When the patients were evaluated as preeclampsia (þ) and

preeclampsia (�) preterms, cord blood VEGF, sVEGFR-1

and VEGF/sVEGFR-1 concentrations were insignificant. Our

results also suggested that VEGF and sVEGFR-1 levels were

related with the severity of RDS or lung maturation but not

with the presence or absence of preeclampsia. This suggestion

was also supported with VEGF, sVEGFR-1 concentrations

and VEGF/sVEGFR-1 ratios of TAF, that all of them were

significantly higher in preterms with sRDS, apart from

preeclampsia.

Studies investigating the relation between preeclampsia

and the occurrence of RDS depend only on the incidence of

RDS in the newborns of hypertensive mothers [14–18,34]. To

our knowledge, our study is the first that investigates the

relationship between the occurrence of RDS and preeclampsia

on the basis of VEGF, sVEGFR-1 concentrations and VEGF/

sVEGFR-1 ratios both in cord blood and TAF. According to

our results, preterm babies of preeclamptic mothers had the

same probability of having sRDS as newborns of normoten-

sive mothers, suggesting that preeclampsia may not protect

against the development of sRDS and fetal lung maturity

seems not to be accelerated in preeclampsia.

In conclusion, preeclampsia seems not to have an import-

ant effect on VEGF and sVEGFR-1 concentrations of

Table 3. VEGF and sVEGFR-1 levels in the TAF of sRDS preterms.

VEGF and VEGF/sVEGFR-1 levelsin TAF

Preeclampsia(þ)sRDS (n:9)

Preeclampsia(�)sRDS (n:10) p**

VEGF (pg/ml)* 25 (10.5–98.3) 43.5 (9.7–1043.8) 0.26sVEGFR-1 (pg/ml)* 234 (50–1936) 222 (54–1010) 0.96VEGF/sVEGFR-1

(pg/ml)*0.10 (0.01–4.08) 0.19 (0.05–5.17) 0.48

*Median (min–max).

982 S. Kalay et al. J Matern Fetal Neonatal Med, 2013; 26(10): 978–983

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newborns both in cord blood and in TAF. Low VEGF and

high sVEGFR-1 concentrations seem to be associated with the

severity of RDS irrespective of preeclampsia, suggesting that

VEGF may be one of the main components of lung

maturation. However, more clinical or experimental studies

are necessary in order to obtain a definitive conclusion about

the effect of VEGF on lung maturation.

Declaration of interest

The authors report no conflicts of interest. The authors alone

are responsible for the content and writing of the paper.

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DOI: 10.3109/14767058.2013.766692 VEGF and its soluble receptor VEGFR-1 in preterm newborns 983

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