PEDIATRICS Vol. 122 No. 2 August 2008, pp. 340-346 (doi:10.1542/peds.2007-1941)
ARTICLE |
Placental Growth Factor and Vascular Endothelial Growth Factor Receptor-2 in Human Lung Development
a Hospital for Children and Adolescents
b Departments of Surgery
c Pathology
d Plastic Surgery, University of Helsinki, Helsinki, Finland
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ABSTRACT |
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OBJECTIVE. We examined the pulmonary expression of 2 proangiogenic factors, namely, placental growth factor and vascular endothelial growth factor receptor-2, during lung development and acute and chronic lung injury in newborn infants.
METHODS. Six groups were included in an immunohistochemical study of placental growth factor and vascular endothelial growth factor receptor-2, that is, 9 fetuses, 4 preterm and 8 term infants without lung injury who died soon after birth, 5 preterm infants with respiratory distress syndrome of <2 days and 7 with respiratory distress syndrome of >10 days, and 6 with bronchopulmonary dysplasia. Placental growth factor concentrations in tracheal aspirate fluid were measured in 70 samples from 20 preterm infants during the first postnatal week.
RESULTS. In immunohistochemical analyses, placental growth factor staining was seen in bronchial epithelium and macrophages in all groups. Distal airway epithelium positivity was observed mostly in fetuses and in preterm infants who died soon after birth. Vascular endothelial growth factor receptor-2 staining was seen in vascular endothelium in all groups and also in lymphatic endothelium in fetuses. Vascular endothelial growth factor receptor-2 staining in arterial endothelium was associated with higher and staining in venous endothelium with lower gestational age. In capillaries, less vascular endothelial growth factor receptor-2 staining was seen in bronchopulmonary dysplasia. The mean placental growth factor protein concentration in tracheal aspirate fluid during the first postnatal week was 0.64 ± 0.42 pg/mL per IgA-secretory component unit. Concentrations during the first postnatal week were stable. Lower placental growth factor concentrations correlated with chorioamnionitis and lactosyl ceramide positivity.
CONCLUSIONS. The vascular endothelial growth factor receptor-2 staining pattern seems to reflect ongoing differentiation and activity of different endothelia. Lower vascular endothelial growth factor receptor-2 expression in capillary endothelium in bronchopulmonary dysplasia might be a reflection of the dysregulation of vascular development that is characteristic of bronchopulmonary dysplasia.
Key Words: lung development • neonatal • respiratory • bronchopulmonary dysplasia
Abbreviations: BW—birth weight • BPD—bronchopulmonary dysplasia • GA—gestational age • PlGF—placental growth factor • RDS—respiratory distress syndrome • TAF—tracheal aspirate fluid • VEGF—vascular endothelial growth factor • VEGFR—vascular endothelial growth factor receptor • IgA-SC—secretory component of IgA
Human placental growth factor (PlGF) initially was located in the human placenta1 but also has been located in heart and lung. PlGF mediates its actions through vascular endothelial growth factor receptor (VEGFR)-1.2 VEGFR-2 is a receptor tyrosine kinase3 that binds vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D and is recognized as the primary receptor transmitting signals in endothelial cells.4,5 It has been suggested that PlGF boosts angiogenesis by binding to VEGFR-1, leaving a higher concentration of free VEGF-A that can bind to VEGFR-2.6 In addition, PlGF seems to have a distinct angiogenic signaling pathway through VEGFR-1.7–9
An infant born early in the third trimester of gestation has poorly developed lungs; the alveoli are just forming, surfactant production has only recently begun, and the capillary bed is poorly developed. Birth at this stage interrupts normal development of the lung in infants of very low birth weight (BW).10 The development of bronchopulmonary dysplasia (BPD) may be attributable to disruption of vascular development by premature birth.11,12 VEGF-A participates in alveolarization in animals.13,14 Moreover, in preterm infants, high pulmonary concentrations of VEGF-A during postnatal days 4 to 7 are associated with lower incidence of BPD.15
We wanted to study the roles of these 2 proangiogenic factors, PlGF and VEGFR-2, that participate in VEGF-A-orchestrated angiogenesis during lung development and in lung injury. Therefore, we evaluated whether postnatal PlGF concentrations in tracheal aspirate fluid (TAF) were associated with parameters reflecting development of respiratory distress syndrome (RDS) or BPD. We also evaluated whether PlGF and VEGFR-2 expression patterns changed during lung development, with and without lung injury.
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METHODS |
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Ethics Approval
All studies were approved by the ethics committee of the Hospital for Children and Adolescents, University Central Hospital (Helsinki, Finland).
Patients in the Immunohistochemical Study
Thirty-nine subjects were included in the PlGF and VEGFR-2 immunohistochemical study. Samples were analyzed in 6 groups, as follows: 9 fetal subjects (gestational age [GA]: 18.1 ± 2.6 weeks; BW: 194 ± 122 g), 4 preterm control subjects (GA: 24.6 ± 2.9 weeks; BW: 788 ± 341 g), 8 term control subjects (GA: 38.9 ± 1.7 weeks; BW: 3411 ± 608 g), 5 early RDS subjects (GA: 26.8 ± 1.9 weeks; BW: 799 ± 464 g; age at death: 1.3 ± 0.7 days), 7 late RDS subjects (GA: 26.8 ± 1.7 weeks; BW: 692 ± 151 g; age at death: 11.3 ± 2.8 days), and 6 BPD subjects (GA: 28.2 ± 2.3 weeks; BW: 892 ± 177 g; age at death: 207 ± 82 days). Samples were collected between March 1991 and June 2000. Infants in the preterm control group did not suffer from RDS and died within 2 hours after birth; causes of premature delivery and death included spontaneous abortion, acute asphyxia, placental ablation, and feto-fetal transfusion (donor). The early RDS group included preterm infants who died within 2 days after birth. The late RDS group included preterm infants who died >10 days after birth but did not meet the criteria for BPD. BPD was diagnosed clinically as a need for supplemental oxygen at the age of 36 gestational weeks, in addition to chest radiographic findings typical of BPD16 and postmortem histologic findings. The patients in both the RDS and BPD groups died as a result of the lung disease. Fetuses and control subjects had macroscopically and microscopically normal lungs; the microscopic findings did not include hyaline membranes characteristic of lung injury present in RDS. Autopsies were performed within 4 days after death (Table 1).
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Patients in the TAF Sample Study
A series of samples were collected from 20 preterm infants. Nine patients who subsequently developed BPD and 11 GA- and BW-matched patients who survived without BPD were selected. BPD was defined as stated above. All of the infants included were intubated at birth because of failure to establish spontaneous ventilation, and none of the patients in the study group received dexamethasone during the study period (Table 2).
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Immunohistochemical Analyses of PlGF and VEGFR-2
Lung samples were obtained as described previously.17 Sections (5 µm) were deparaffinized in xylene and rehydrated through graded concentrations of alcohol and distilled water. The sections were then treated in a 700-W microwave oven for 4 x 5 minutes, in Tris-EDTA solution, and the slides were cooled at room temperature for 20 minutes and washed in 1:10 phosphate-buffered saline/distilled water solution. PlGF-specific antibody was used at a 1:100 dilution (antibody ab9542, rabbit polyclonal antibody to human PlGF; Novus Biologicals, Littleton, CO). VEGFR-2-specific antibody was used at a 1:60 dilution (antibody AF357, anti-human VEGFR-2 antibody; R&D Systems, Minneapolis, MN), following the instructions provided by the manufacturer. Bound antibody was visualized by using the avidin-biotin complex immunoperoxidase technique (Elite ABC kit, Vectastain; Vector, Burlingame, CA). Sections were incubated with the biotinylated second-layer antibody and peroxidase-labeled avidin-biotin complex for 30 minutes each. All dilutions were made in phosphate-buffered saline (pH 7.2), and all incubations in the avidin-biotin complex method were conducted in humidified chambers at room temperature. Between each step in the staining process, slides were rinsed in 3 changes of phosphate-buffered saline. Peroxidase staining was visualized with 3-amino-9-ethylcarbazole (A-5754; Sigma, St Louis, MO), 0.2 mg/mL in 0.05 mol/L acetate buffer containing 0.03% perhydrol (pH 5.0), at room temperature for 15 minutes. Sections were rinsed in tap water for 10 minutes. To complete the process, sections were counterstained in Mayer's hematoxylin, cleared in tap water, and mounted in aqueous mounting medium (Aquamount; BDH, Poole, England). Negative control samples were prepared with omission of the primary antibody, and a known antibody-positive section (fetal liver) was included as a positive control sample.
TAF Sample Collection
Samples of TAF were collected once daily through standardized routine tracheal lavage, as described previously.15 A total of 70 samples collected from 20 patients during the first postnatal week were used for analysis.
Analyses of PlGF and Secretory Component of IgA in TAF
PlGF was analyzed with a human PlGF immunoassay kit (R&D Systems). To estimate the in situ pulmonary concentration of PlGF, a correction for dilution of the TAF sample was calculated by using the concentration of the secretory component of IgA (IgA-SC) in TAF. The concentration of IgA-SC in lung secretions is independent of capillary leak, and the concentration of IgA-SC in TAF samples is independent of respiratory distress or GA.18 IgA-SC concentrations were determined in direct enzyme-linked immunosorbent assays, with secretory IgA isolated from human colostrum as a standard. The IgA-SC standards were kindly provided by Dr B. Götze-Speer and Prof C. Speer (University Children's Hospital, Würzburg, Germany).
Statistical Analyses
Nonparametric methods were used in analyses of TAF data, including the Mann-Whitney U test, the Kruskal-Wallis test, and simple regression analysis. Values represent mean ± SD for patient data, mean ± SEM for experimental results, and frequencies for categorical variables. Variables with skewed distribution were logarithmically transformed before analyses, but values presented in the text and tables are nontransformed. P values of <.05 were considered statistically significant. In analyses of immunohistochemical data, contingency table tests and t tests were used. All calculations were performed with StatView 5.1 (SAS Institute, Cary, NC).
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RESULTS |
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Immunohistochemical Analysis of PlGF
Positive staining for PlGF was observed in macrophages in 34 (87%) of the 39 cases. Macrophages were stained throughout the samples in most cases. Bronchial epithelial positivity was found in 24 (62%) of the 39 cases. Staining was visible in large bronchi and in small bronchioli. Staining was observed both apically and more uniformly within epithelial cells. No differences existed between groups in bronchial epithelial staining. Distal airway epithelial positivity was observed in 11 (28%) of the 39 cases. Distal airway positivity was seen almost exclusively in fetuses and in preterm infants who died soon after birth, with or without lung injury. Epithelial cell staining was observed apically in fetuses, whereas staining was distributed more uniformly within the epithelial cells in preterm infants. Positive PlGF staining in distal airway epithelium was associated with lower GA (20.9 ± 4.4 weeks vs 29.7 ± 6.7 weeks; P = .0003) and with lower BW or weight at the time of abortion (361 ± 250 g vs 1515 ± 1219 g; P = .0060). Gender or postmortem time to autopsy did not correlate with positive PlGF staining (Figs 1 and 2).
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Immunohistochemical Analysis of VEGFR-2
Positive staining for VEGFR-2 was seen in vascular endothelium in 32 (82%) of the 39 cases. Positive staining in arterial endothelium was visible in 9 (23%) of the 39 cases, and it associated with higher GA (32.1 ± 6.9 weeks vs 25.8 ± 6.9 weeks; P = .021) and with higher BW or weight at the time of abortion (2008 ± 1383 g vs 943 ± 1069 g; P = .019). Positive staining in venous endothelium was visible in 27 (69%) of the 39 cases, and it was associated with lower GA (25.5 ± 6.5 weeks vs 31.1 ± 7.8 weeks; P = .024) and with lower BW or weight at the time of abortion (900 ± 963 g vs 1839 ± 1502 g; P = .024). Positive staining of VEGFR-2 in capillary endothelium was seen in 29 (74%) of the 39 cases. Between groups, capillary positivity was >60% except in the BPD group, where positivity was 33%. Capillary VEGFR-2 positivity was associated with lower postnatal age of death (12 ± 41 days vs 96 ± 127 days; P = .0034). VEGFR-2 staining was also seen in lymphatic vessel-resembling structures in 7 (18%) of the 39 cases. Of the 9 fetuses, positivity in lymphatic structures was seen in 5 (55%). All fetuses that exhibited positive lymphatic endothelial staining were at <21 weeks of gestation (GA: 17.0 ± 2.7 weeks). Gender or postmortem time to autopsy did not correlate with positive VEGFR-2 staining (Figs 1 and 3).
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PlGF Protein Levels in TAF
The mean PlGF protein concentration in TAF during the first postnatal week was 0.64 ± 0.42 pg/mL per IgA-SC unit; the mean PlGF levels during the first postnatal week were used in statistical analyses (Fig 4). Of the 20 infants, 7 were born from pregnancies complicated by chorioamnionitis or premature rupture of the membranes. Those infants had lower mean PlGF levels in TAF than did infants with no maternal infections or preeclampsia (P = .015).
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Lactosyl ceramide has been demonstrated in large amounts in granulocytes and inflamed fetal membranes. It was measured in 10 infants with thin layer chromatography, as described previously.19 Lactosyl ceramide levels correlated positivity with lower PlGF levels in TAF (P = .027). No correlations were found between BW or GA or between pH or base excess in cord artery blood and PlGF levels in TAF. Duration of mechanical ventilation, mean concentration of inspired oxygen during the first postnatal week, and subsequent development of BPD did not correlate with PlGF concentrations in TAF. PlGF concentrations in TAF did not correlate with prenatal betamethasone treatment, indomethacin treatment, or subsequent need for dexamethasone therapy (Table 2).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In this study, we showed that PlGF protein is expressed consistently in airway epithelium during lung development. Expression was seen throughout lung epithelium from large proximal bronchi to cuboidal and alveolar epithelia. PlGF protein expression was detected in the fetal lung as early as 14 weeks of gestation. In addition, a significant amount of PlGF protein was detected in TAF from human preterm infants during the first postnatal week. PlGF–/– mice were shown to exhibit normal vascular development.20 In our study, PlGF protein expression in distal airway epithelium was restricted to fetuses and preterm infants, and there were correlations between PlGF expression in alveolar and cuboidal epithelia and lower BW and GA. However, levels of PlGF in TAF did not correlate with GA or BW. PlGF mediates its effects mainly through VEGFR-1.2 Interestingly, positive VEGFR-1 staining noted previously resembles the PlGF staining seen in this study; positive staining could be seen throughout the developing lung in fetuses and preterm infants, whereas staining was not seen adjacent to distal epithelium in term infants.17 We conclude that, in the developing human lung, PlGF is expressed continuously throughout the fetal period. There is, however, a change in PlGF expression patterns from distal epithelium to more-proximal epithelium during development, which suggests that, at least during the later stages of development, PlGF asserts its effects mainly on conducting airways.
The development of BPD has been suggested to result from disruption of vascular development, which leads to an arrest of lung alveolarization.11,12 Preterm infants who develop BPD have lower levels of VEGF-A than do those who do not develop BPD.15 PlGF boosts angiogenesis through binding of VEGFR-1 and subsequent activation of VEGFR-2 by VEGF-A.6 It has been shown that PlGF is induced to assist VEGF-A in pathologic angiogenesis in adults.20 Pathologic angiogenesis is often associated with inflammation, and PlGF itself is an attractant of inflammatory cells.21 Preterm birth is often associated with maternal chorioamnionitis; histologic chorioamnionitis is related inversely to GA, being well above 50% at GA of 20 to 24 weeks.22 In addition, mechanical ventilation elicits an inflammatory state in the preterm lung. The injury caused by ventilation leads to the release of proinflammatory cytokines, which in turn activate and attract neutrophils and phagocytes to the site of injury.23,24 In view of this, it was reasonable to expect a postpartum elevation of PlGF protein levels. Interestingly, in our patients, the concentrations of PlGF in TAF during the first postnatal week were stable (Fig 4). Moreover, PlGF protein concentrations in TAF were not elevated in conjunction with parameters reflecting RDS or BPD. Instead, infants born from pregnancies complicated by chorioamnionitis or premature rupture of the membranes and those who tested positive for lactosyl ceramide had lower PlGF levels in TAF during the first postnatal week. We showed previously that lower VEGF concentrations in TAF after birth correlated with the development of BPD.15 In view of our finding, it is possible to draw the conclusion that inflammation in the lung perinatally hinders alveolarization through decreased angiogenesis, mirrored by the decrease in PlGF concentrations in TAF, and inflammation could be an important factor in the development of BPD. Therefore, PlGF seems to have a constitutional role in the developing human lung, various states of inflammation perinatally lead to decreased levels of PlGF, and inflammation could contribute to the pathogenesis of BPD.
We found constant VEGFR-2 staining in airway endothelium. However, staining in different types of endothelium varied during development. We detected some VEGFR-2 expression in lymphatic endothelium, mostly in fetuses. In addition to vascular endothelial development, VEGFR-2 has been shown to have other roles. In mice, VEGFR-2 is essential for the development of hematopoietic and endothelial cells.25 In early stages of development, there seems to be some overlapping of vasculogenesis, angiogenesis, and lymphangiogenesis; VEGF-C binds VEGFR-2, in addition to VEGFR-3, in early stages of lung development,26 and VEGF-C may play a role in the development of the vascular tree.27 Also, VEGFR-3, which is strictly lymphangiogenic later in development, is vital to venous development in mouse lung.27 VEGFR-2 was detected previously on lymphatic endothelial cells.28 In our study, we found more staining for VEGFR-2 in venous endothelium in more-immature lungs, whereas more staining in arterial endothelium was seen in more-mature lungs (Fig 3). VEGFR-2 expression is downregulated in mature vascular endothelium and is upregulated again in angiogenic vessels.29 The VEGFR-2 staining in lymphatic and venous endothelia during the early stages of lung development and arterial staining during later development could reflect the ongoing differentiation and activity of different endothelia.
Capillary endothelial staining was fairly constant, the only exception being that staining of capillary and septal endothelia was decreased in BPD. This could be explained by the vascular hypothesis of BPD,11,12 according to which deranged angiogenesis leads to dilated distal airspaces and decreased alveolar surface area attributable to alveolar and septal apoptosis. VEGFR-2 expression has been shown to be guided by VEGF-A.30,31 We showed previously that lower VEGF-A concentrations in TAF correlated with the development of BPD.15 According to Shalaby et al,25 VEGFR-2-deficient mice fail to develop blood islands, and vasculogenesis is seriously impaired. This mutation leads to death in utero between postcoital days 8.5 and 9.5. More recently, Hosford et al32 demonstrated that hyperoxia (>95%) administered postnatally in neonatal rats led to decreased mRNA expression of VEGF, as well as both VEGFR-1 and VEGFR-2, from postnatal day 6 onward, compared with rats raised in a normoxic (21%) environment. These changes in mRNA expression then led to decreased VEGF, VEGFR-1, and VEGFR-2 protein expressions seen on postnatal days 12 and 14, inhibiting angiogenesis and subsequently alveolarization.32 Levels of angiopoietin-2, which has antiangiogenic effects by destabilizing vessel walls, inducing endothelial cell apoptosis, and increasing vascular permeability, have been shown to increase in TAF in infants who develop BPD.33 According to views on BPD, it is thought that impaired angiogenesis at critical stages of lung development hinders lung alveolarization and is central in the pathophysiologic processes of BPD.12 Evidence also suggests that impaired angiogenesis does not contribute to the pathogenesis of BPD.34,35 De Paepe et al36 also concluded that no mismatch between alveolar epithelium and vascular endothelium existed in BPD; however, that study was quantitative rather than qualitative in its approach and did not provide an opportunity to study vascular structures in greater detail. Additional work is needed for better understanding of the many aspects of BPD and the roles of the different proangiogenic and antiangiogenic growth factors. However, we think that decreased VEGFR-2 expression in septal capillaries is a sign of dysregulation of vascular development characteristic of BPD.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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PlGF is expressed constantly throughout lung development. Staining during earlier stages of development is seen throughout the lung epithelium, whereas staining in the later stages of development is restricted to proximal airway epithelium, which suggests that, at least during the later stages of development, PlGF asserts its effects mainly on conducting airways. Various states of inflammation perinatally lead to decreased levels of PlGF; this may be one of the mechanisms through which inflammation contributes to the pathogenesis of BPD. VEGFR-2 also is expressed constantly throughout human lung development. The VEGFR-2 expression profile changes with lung maturation; staining in immature lung is seen in lymphatic and venous endothelia, whereas staining in more-mature lung is seen mostly in arterial endothelium. This is seen as a reflection of the ongoing differentiation and activity of different endothelia during development. Expression in septal and capillary endothelium is decreased in BPD, which may illustrate an aspect of the pathogenesis of BPD.
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ACKNOWLEDGMENTS |
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This work was supported by the Sigrid Jusélius Foundation, Finska Läkaresällskapet, Nylands Nation, Helsinki University Central Hospital Research Fund, and Foundation for Pediatric Research.
We thank the personnel of the NICU and the neonatal nursery of the Hospital for Children and Adolescents for their kind cooperation. Marjatta Vallas, Elina Laitinen, and Päivi Peltokangas are thanked for excellent technical assistance. Dr B. Götze-Speer and Prof C. Speer (University Children's Hospital, Würzburg, Germany) are thanked for generous help with IgA-SC standardization.
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FOOTNOTES |
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Accepted Dec 15, 2007.
Address correspondence to Joakim Janér, MD, Hospital for Children and Adolescents, PO Box 281, 00029 HUS, Helsinki, Finland. E-mail: joakim.janer{at}helsinki.fi
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject The participation of PlGF and VEGFR-2 in human lung development and possibly in the development of BPD is not clear.
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| What This Study Adds This study describes the expression of PlGF and VEGFR-2 in the developing human lung and during BPD. Immunohistochemical staining and tracheal aspirate fluid concentrations were analyzed.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
- Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor.
Proc Natl Acad Sci USA. 1991;88
(20):9267
–9271
[Abstract/Free Full Text] - Ylä-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nat Med. 2003;9 (6):694 –701[CrossRef][Web of Science][Medline]
- Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene. 1991;6 (9):1677 –1683[Web of Science][Medline]
- Wise LM, Veikkola T, Mercer AA, et al. Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1.
Proc Natl Acad Sci USA. 1999;96
(6):3071
–3076
[Abstract/Free Full Text] - Zachary I, Gliki G. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family.
Cardiovasc Res. 2001;49
(3):568
–581
[Abstract/Free Full Text] - Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to flt-1 but not to flk-1/KDR.
J Biol Chem. 1994;269
(41):25646
–25654
[Abstract/Free Full Text] - Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors.
FASEB J. 1999;13
(1):9
–22
[Abstract/Free Full Text] - Shibuya M, Ito N, Claesson-Welsh L. Structure and function of vascular endothelial growth factor receptor-1 and -2. Curr Top Microbiol Immunol. 1999;237 :59 –83[Web of Science][Medline]
- Cao Y, Linden P, Shima D, Browne F, Folkman J. In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor. J Clin Invest. 1996;98 (11):2507 –2511[Web of Science][Medline]
- Zoban P, Cerny M. Immature lung and acute lung injury. Physiol Res. 2003;52 (5):507 –516[Web of Science][Medline]
- Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res. 1999;46 (6):641 –643[Web of Science][Medline]
- Abman SH. Bronchopulmonary dysplasia: "a vascular hypothesis." Am J Respir Crit Care Med. 2001;164 (10):1755–1756
- Akeson AL, Cameron JE, Le Cras TD, Whitsett JA, Greenberg JM. Vascular endothelial growth factor-A induces prenatal neovascularization and alters bronchial development in mice. Pediatr Res. 2005;57 (1):82–88
- Compernolle V, Brusselmans K, Acker T, et al. Loss of HIF-2
and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice.
Nat Med. 2002;8
(7):702
–710[Web of Science][Medline] - Lassus P, Ristimäki A, Ylikorkala O, Viinikka L, Andersson S. Vascular endothelial growth factor in the human preterm lung.
Am J Respir Crit Care Med. 1999;159
(5):1429
–1433
[Abstract/Free Full Text] - Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period.
Pediatrics. 1988;82
(4):527
–532
[Abstract/Free Full Text] - Lassus P, Turanlahti M, Heikkilä P, et al. Pulmonary endothelial growth factor and Flt-1 in fetuses, in acute and chronic lung disease, and in persistent pulmonary hypertension of the newborn.
Am J Respir Crit Care Med. 2001;164
(10):1981
–1987
[Abstract/Free Full Text] - Watts CL, Fanaroff AA, Bruce MC. Elevation of fibronectin levels in lung secretions of infants with respiratory distress syndrome and development of bronchopulmonary dysplasia. J Pediatr. 1992;120 (4):614 –620[CrossRef][Web of Science][Medline]
- Hallman M, Bry K, Pitkanen O. Ceramide lactoside in amniotic fluid: high concentration in chorioamnionitis and in preterm labor. Am J Obstet Gynecol. 1989;161 (2):313 –318[Web of Science][Medline]
- Carmeliet P, Moons L, Luttun A, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001;7 (5):575 –583[CrossRef][Web of Science][Medline]
- Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6 (4):389 –395[CrossRef][Web of Science][Medline]
- Lahra MM, Jeffery HE. A fetal response to chorioamnionitis is associated with early survival after preterm birth. Am J Obstet Gynecol. 2004;190 (1):147 –151[CrossRef][Web of Science][Medline]
- Jobe AH. Glucocorticoids, inflammation and the perinatal lung. Semin Neonatol. 2001;6 (4):331 –342[CrossRef][Medline]
- Turunen R, Nupponen I, Siitonen S, Repo H, Andersson S. Onset of mechanical ventilation is associated with rapid activation of circulating phagocytes in preterm infants.
Pediatrics. 2006;117
(2):448
–454
[Abstract/Free Full Text] - Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376 (6535):62 –66[CrossRef][Web of Science][Medline]
- Joukov V, Pajusola K, Kaipainen A, et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 1996;15 (2):290 –298[Web of Science][Medline]
- Dumont DJ, Jussila L, Taipale J, et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3.
Science. 1998;282
(5390):946
–949
[Abstract/Free Full Text] - Mäkinen T, Veikkola T, Mustjoki S, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001;20 (17):4762 –4773[CrossRef][Web of Science][Medline]
- Partanen TA, Alitalo K, Miettinen M. Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer. 1999;86 (11):2406 –2412[CrossRef][Web of Science][Medline]
- Gerhardt H, Golding M, Fruttiger M, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia.
J Cell Biol. 2003;161
(6):1163
–1177
[Abstract/Free Full Text] - Hiratsuka S, Kataoka Y, Nakao K, et al. Vascular endothelial growth factor A (VEGF-A) is involved in guidance of VEGF receptor-positive cells to the anterior portion of early embryos.
Mol Cell Biol. 2005;25
(1):355
–363
[Abstract/Free Full Text] - Hosford GE, Olson DM. Effects of hyperoxia on VEGF, its receptors, and HIF-2 in the newborn rat lung.
Am J Physiol Lung Cell Mol Physiol. 2003;285
(1):L161
–L168
[Abstract/Free Full Text] - Bhandari V, Choo-Wing R, Lee CG, et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med. 2006;12 (11):1286 –1293[CrossRef][Web of Science][Medline]
- Ambalavanan N, Novak ZE. Peptide growth factors in tracheal aspirates of mechanically ventilated preterm neonates. Pediatr Res. 2003;53 (2):240 –244[CrossRef][Web of Science][Medline]
- Asikainen TM, Ahmad A, Schneider BK, White CW. Effect of preterm birth on hypoxia-inducible factors and vascular endothelial growth factor in primate lungs. Pediatr Pulmonol. 2005;40 (6):538 –546[CrossRef][Web of Science][Medline]
- De Paepe ME, Mao Q, Powell J, et al. Growth of pulmonary microvasculature in ventilated preterm infants.
Am J Respir Crit Care Med. 2006;173
(2):204
–211
[Abstract/Free Full Text]
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