Neonatology

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Low Urine Vascular Endothelial Growth Factor Levels Are Associated with Mechanical Ventilation, Bronchopulmonary Dysplasia and Retinopathy of Prematurity

Levesque B.M.a,b,i · Kalish L.A.c, i · Winston A.B.a · Parad R.B.a,d,i · Hernandez-Diaz S.e · Phillips M.a, d · Zolit A.d · Morey J.a, d · Gupta M.a,f,i · Mammoto A.g, i · Ingber D.E.g-i · Van Marter L.J.a,d,i

Author affiliations

aDivision of Newborn Medicine, Boston Children's Hospital, bDivision of Neonatology, St. Elizabeth's Medical Center, cClinical Research Center, Boston Children's Hospital, dDepartment of Newborn Medicine, Brigham and Women's Hospital, eHarvard School of Public Health, fDepartment of Neonatology, Beth Israel Deaconess Medical Center, gVascular Biology Program, Boston Children's Hospital, Harvard Medical School, hWyss Institute for Biologically Inspired Engineering at Harvard University, and iHarvard Medical School, Boston, Mass., USA

Corresponding Author

Bernadette M. Levesque, MD

Division of Neonatology, St. Elizabeth's Medical Center

736 Cambridge Street, Quinn 207

Boston, MA 02135 (USA)

E-Mail Bernadette.levesque@childrens.harvard.edu

Keywords: Vascular endothelial growth factorBronchopulmonary dysplasiaRetinopathy of prematurityMechanical ventilationFraction of inspired oxygenEnzyme-linked immunosorbent assayBiomarker

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Neonatology 2013;104:56-64
https://doi.org/10.1159/000351040

Abstract

Background: Organ-specific vascular endothelial growth factor (VEGF) expression is decreased during the pathogenesis of bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) several weeks before either disease can be diagnosed. Early measurement of organ-specific tissue VEGF levels might allow identification of infants at high risk for these diseases, but is not clinically feasible. Urine VEGF is easily measured and useful in early diagnosis of several diseases. Objectives: Our aims were to assess the correlation of urine VEGF levels measured in the first postnatal month with subsequent BPD or ROP diagnosis and to determine whether various infant characteristics influence urine VEGF levels. Methods: 106 subjects born at <29 weeks' gestation and surviving to 36 weeks' postmenstrual age were selected from an existing database and biorepository. Urine VEGF and total protein were measured in 2-3 samples per subject. Results: Urine VEGF/protein levels increased by 72% per week (p < 0.0001) during the first postnatal month. In multivariable analysis controlling for postnatal age, lower VEGF/protein was associated with higher levels of mechanical respiratory support (p = 0.006), male gender (p = 0.001) and early sepsis (p = 0.003) but not with fraction of inspired oxygen. Lower urine VEGF/protein and mechanical ventilation were each associated with BPD and ROP. In analyses adjusted for respiratory support, lower urine VEGF/protein and ROP remained associated but urine VEGF/protein and BPD did not. Conclusions: Low urine VEGF/protein levels in the first postnatal month are associated with mechanical ventilation, BPD, and ROP.

© 2013 S. Karger AG, Basel

Introduction

Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are common complications of prematurity that result from abnormal postnatal development of the lung and eye, respectively. While the developmental programs of each organ are unique, both are critically dependent on angiogenesis, and disruption of normal angiogenesis is central to the pathogenesis of both diseases.

BPD is a chronic lung disease characterized by alveolar simplification and capillary dysplasia [1] that affects 42% of infants born before 29 weeks' gestation [2]. BPD results, in part, from failure of postnatal secondary septation, a morphogenic process that utilizes angiogenesis to subdivide the saccular airspaces of the immature lung into alveoli [1]. Lung angiogenesis is largely regulated by vascular endothelial growth factor (VEGF) [3], and VEGF expression is suppressed in BPD [4,5]. While the pathogenesis of BPD is multifactorial, augmenting VEGF signaling and angiogenesis can prevent BPD in animal models [6,7,8] and might do the same in human infants.

ROP is a neoproliferative retinopathy caused by abnormal postnatal development of the retina that affects 59% of infants born before 29 weeks' gestation [2]. Retinal blood vessels normally develop by VEGF-driven angiogenesis [9]. In early stages of ROP, VEGF is suppressed and the retinal vessels stop growing [10]. In later stages, hypoxia of the avascular retina triggers VEGF overexpression and proliferative neovascularization [9]. Current treatments reduce VEGF signaling during late ROP [11], but augmenting VEGF expression in early ROP can prevent both the loss of retinal vessels and subsequent neoproliferation in animal models [10,12] and has been proposed as a preventative treatment for human infants [9].

Both BPD and ROP are characterized by VEGF suppression after preterm birth and afflict the same population of infants. Each might be prevented by early VEGF augmentation. We hypothesized that urine VEGF levels are lower in the first postnatal month among premature infants who later develop BPD or ROP. Our study aims were to assess the association between urine VEGF and subsequent diagnosis of BPD and/or ROP and to evaluate the impact of various subject characteristics on urine VEGF levels.

Materials and Methods

Study Population

Subjects were selected from the Boston Children's Hospital Specialized Centers of Research (SCOR) in lung biology database of infants born before 29 weeks' gestation. Eligible subjects were born at Brigham and Women's Hospital (BWH), survived to 36 weeks' postmenstrual age (PMA), and had ≥2 urine samples of adequate volume separated by ≥4 days obtained during the first postnatal month. Our goal was to enroll ≥100 subjects and process ≥200 urine samples. BPD was defined as need for supplemental oxygen at 36 weeks' PMA. Severe ROP was defined as stage 3 or greater. The BWH Institutional Review Board approved the collection of clinical data and urine samples without informed consent. Once subjects were selected, urine samples were removed from the biorepository, marked with identification and sample numbers, and given to the basic science researchers (B.M.L., A.M., D.E.I.) without corresponding clinical data; urine VEGF and protein were measured. De-identified clinical data were submitted by the SCOR group researchers and laboratory data were submitted by the basic science researchers to an independent statistician (L.A.K.) for analysis.

VEGF Measurement

Urine samples were collected using cotton balls placed in the diapers of subjects and stored frozen at -80°C. VEGF was measured by enzyme-linked immunosorbent assay (ELISA) (R&D Human Quantikine ELISA, Minneapolis, Minn., USA) in duplicate samples and averaged values were recorded. Because the immature kidneys of very premature infants allow the passage of excess protein in the urine [13], total urine protein was measured using BD protein assay (Becton Dickinson Co., Franklin Lakes, N.J., USA) to provide a physiologic denominator for urine VEGF protein.

Statistical Analysis

Parametric statistical analyses were performed using logarithmically transformed values because urine VEGF and VEGF/protein data were not normally distributed; results were transformed back to original units for reporting.

Linear random effects models were used to evaluate associations between VEGF or VEGF/protein and gestational age (GA), postnatal age (PNA), and PMA. Models with PNA included both random intercepts and slopes. Associations of VEGF/protein with individual subject characteristics were tested using separate mixed effects models while adjusting for PNA. Potential interactions between each characteristic and PNA were evaluated with the Wald test. Significantly associated characteristics were then considered in multivariate analysis while adjusting for PNA. For reporting, each subject's VEGF/protein measurements were averaged and the medians and quartiles of these values within subgroups were presented. Model-based associations with age were illustrated by plotting the regression lines showing VEGF/protein levels in original units on a multiplicative scale.

We evaluated respiratory support and fraction of inspired oxygen (FiO2) both as time-fixed (at day 7) and time-varying (on sample day) covariates. To investigate the joint effects of VEGF/protein and day 7 respiratory support on BPD and ROP outcomes, we used logistic regression models using the average of each subject's VEGF/protein levels. We then contrasted odds ratios (ORs) representing the associations between the predictors (VEGF/protein and respiratory support) and outcomes from separate unadjusted models versus from a single multivariable model.

All analyses were performed using SAS 9.2. p values are two-sided and considered significant when p < 0.05.

Results

A cohort of 106 subjects was selected (described in table 1) from among 625 eligible SCOR subjects and 257 urine samples were assayed. Cohort subjects were similar to the larger SCOR population in birth weight, GA, gender, and race (data not shown). Each subject contributed ≥2 samples; 45 subjects contributed 3. Most samples were obtained in the first 2 postnatal weeks (147, 94, and 16 samples from weeks 1, 2, and ≥3, respectively).

Table 1

Demographic characteristics, perinatal factors and outcomes of cohort (n = 106, except where shown)

http://www.karger.com/WebMaterial/ShowPic/170853

Changes in Urine VEGF by PNA and Maturity

Unadjusted VEGF did not significantly change with increasing GA, PNA, or PMA (data not shown). VEGF/protein increased with increasing GA at birth (↑8.4% per week GA (95% CI +0.5%, +16.9%, p = 0.04), and then increased more rapidly with increasing PNA (↑72% per week (95% CI +48.3%, +99.5%, p < 0.0001). As PMA reflects both GA and PNA, its effect on VEGF/protein was intermediary (↑19.7% per week PMA (95% CI +11.9%, +28.1%, p < 0.0001). VEGF/protein was used for all subsequent analyses, while controlling for PNA and/or developmental maturity as indicated.

Subject Characteristics and Urine VEGF/Protein

We initially explored associations between multiple characteristics or outcomes and urine VEGF/protein while controlling only for PNA (table 2). Subjects on continuous positive airway pressure (CPAP) or mechanical ventilation (MV) at day 7 had 33.2 and 46% lower VEGF/protein values, respectively, compared with subjects receiving no support (fig. 1a). Urine VEGF/protein was also significantly lower in association with greater respiratory support at the time of the sample, but only during the first postnatal week (interaction test, p = 0.0002; fig. 1b). There was no association between urine VEGF/protein and FiO2 on day 7 (table 2, p = 0.19) or at the time of sample (p = 0.47).

Table 2

Association of characteristics or outcomes with VEGF/protein in unadjusted analyses

http://www.karger.com/WebMaterial/ShowPic/170852

Fig. 1

Association between VEGF/protein and respiratory support at day 7 (a) and day of sample (b). RA/NC = Room air or nasal cannula. Analysis includes all available data but regression lines are truncated at day 14 as only 6% of samples contributed data beyond 2 weeks of age.

http://www.karger.com/WebMaterial/ShowPic/170850

Many other factors were significantly associated with VEGF/protein when adjusting only for PNA (table 2), but only gender and early sepsis remained associated after adjusting for PNA and respiratory support on day 7 (table 3). We obtained similar results adjusting for PNA and respiratory support on the day of sample.

Table 3

Association of characteristics or outcomes with VEGF/protein in adjusted analyses

http://www.karger.com/WebMaterial/ShowPic/170851

Association of Urine VEGF with BPD or ROP

Subjects who later developed BPD or ROP had lower urine VEGF/protein values (table 2). Using logistic regression models, we examined the association between VEGF/protein and BPD or ROP while adjusting for respiratory support on day 7. We adjusted only for respiratory support because it was overwhelmingly associated with both VEGF/protein and BPD or ROP, whereas gender and early sepsis were not associated with BPD (both p = 0.56, Fisher's exact test).

A 2-fold decrease in VEGF/protein was associated with a 1.66-fold (95% CI 1.04, 2.65) greater odds of developing BPD (fig. 2a); however, the association was no longer significant once the model was adjusted for respiratory support on day 7 (OR = 1.04, 95% CI 0.58, 1.85). In the analysis of respiratory support, both CPAP and MV were associated with BPD with ORs of 6.72 (95% CI 1.32, 34.3) and 37.6 (95% CI 7.71, 183.2), respectively, compared with no mechanical support. When this model was adjusted for VEGF/protein, the associations between respiratory support and BPD remained virtually unchanged and highly significant. The adjusted analysis yielded similar results if we also adjusted for GA at birth or mean PMA or if we restricted the VEGF/protein values to those collected during the first week of life.

Fig. 2

Logistic regression models for odds of BPD diagnosis (oxygen requirement at 36 weeks' PMA; a) and ROP (stage 3-4 or requiring laser photocoagulation; b). Unadjusted ORs are from separate logistic models, one for VEGF/protein and one for respiratory support at day 7. Adjusted results are from single logistic model including both predictors.

http://www.karger.com/WebMaterial/ShowPic/170849

In a similar analysis of VEGF and severe ROP (fig. 2b), MV was compared to the combined reference group of CPAP and no respiratory support, as there were no infants on CPAP on day 7 who developed severe ROP. A 2-fold decrease in VEGF/protein was associated with a 2.82-fold (95% CI 1.45, 5.48) increased odds of developing severe ROP, and MV was associated with an OR of 27.5 (95% CI 3.47, 217.6). Both ORs were attenuated slightly (14-19%) in adjusted analyses but both remained statistically significant. These conclusions were unchanged if we also adjusted for GA at birth or mean PMA or if we restricted the VEGF/protein values to those collected during the first week of life.

In figure 3, we plotted VEGF/protein values for all subjects using different colors for those who went on to develop BPD or ROP and those who did not. There was substantial overlap between values obtained for affected versus unaffected infants with no apparent cutoff value that distinguished between groups.

Fig. 3

Association between VEGF/protein and development of BPD (a) or ROP (b). Analysis includes all available data but regression lines are truncated at day 14 as only 6% of samples contributed data beyond 2 weeks of age.

http://www.karger.com/WebMaterial/ShowPic/170848

Discussion

We found that urine VEGF/protein increased with increasing PNA. Higher levels of respiratory support were associated with lower VEGF/protein, but only in the first week of life, and VEGF/protein levels were lower in males and in subjects with early sepsis. Infants who later developed BPD or ROP had lower urine VEGF/protein levels than those who did not. Higher levels of respiratory support were strongly and independently associated with both BPD and ROP. In adjusted analyses, the association between lower urine VEGF/protein and BPD was no longer evident once the analysis was adjusted for respiratory support; however, the association between lower urine VEGF/protein and ROP remained significant.

It is well known that hypoxia induces VEGF expression through hypoxia-inducible factor-1α (HIF-1α) signaling [14], and evidence of an association between urine VEGF/protein and FiO2 would have been biologically plausible, but was not found. It is possible that exposure of the newborn infant to room air is sufficient to fully suppress the HIF-1α contribution to VEGF expression, thereby preventing further VEGF suppression with FiO2 >0.21. Or perhaps the VEGF response to FiO2 is simply overwhelmed by the response to MV.

Regulation of VEGF expression by mechanical forces is not as well studied. Until recently, the huge contribution of mechanical forces in regulating gene expression and organ development had not been fully appreciated, but such forces are very important during lung development [15,16,17]. We know that excessive mechanical strain applied to the immature lung with MV alters multiple growth factors and cytokines, disrupts lung development, and leads to BPD [18]. Mechanical strain also regulates lung VEGF expression [19,20,21], and VEGF is significantly reduced in the lungs of ventilated newborn animals [22]. We found a stepwise decrease in urine VEGF/protein associated with a stepwise increase in respiratory support from none to CPAP to MV. This finding is consistent with preliminary in vitro studies showing progressively less VEGF production with increasing levels of cyclic mechanical strain applied to cultured type II pneumocytes [20].

Study infants who later developed BPD or ROP had lower urine VEGF/protein and were exposed to higher levels of respiratory support. The association between lower VEGF/protein and BPD was no longer significant once the model was adjusted for respiratory support, but higher levels of respiratory support remained significantly associated with BPD once the model was adjusted for VEGF/protein. This suggests that while respiratory support appears to decrease urine VEGF/protein, respiratory support increases the odds of developing BPD by some mechanism not reflected in urine VEGF/protein. This mechanism could still possibly involve VEGF if the effect is on matrix-associated lung tissue VEGF that is not measured in the urine. Both VEGF/protein and MV were associated with increased odds of developing ROP. Each of these associations was attenuated slightly in adjusted analyses but remained statistically significant. These results suggest that MV and urine VEGF/protein are independently associated with ROP.

The associations we report are remarkable considering the limitations inherent in measuring urine rather than tissue VEGF. There are several VEGF isoforms, but only the diffusible VEGF isoforms (VEGF121 and VEGF165) can be measured in serum and urine, whereas matrix-bound VEGF189 can be measured only in tissue [23]. Serum VEGF is derived from total body VEGF production, not selectively from the lung or eye, and urine VEGF may not closely reflect serum VEGF [24]. Despite these limitations, and despite the very small sample size of this study, our findings lend further support to several prior studies linking low VEGF expression with MV, BPD, and ROP.

In summary, among this population of extremely premature infants, we found that low urine VEGF/protein levels during the first postnatal month were associated with mechanical respiratory support, BPD, and ROP. Larger, population-based studies would be required to determine sensitivity and specificity of urine VEGF in predicting BPD or ROP. Our results suggest that urine VEGF could be an effective biomarker. In the best-case scenario, urine VEGF could be used to identify patients at risk for BPD or ROP early enough to provide some opportunity to intervene. Potential interventions could include reducing exposure to known causative factors (such as oxygen, MV, inflammation) or new medications currently in development that aim to increase VEGF production (for example, inhibitors of prolyl hydroxylase domain-containing proteins that activate hypoxia-inducible factors [6]). Ideally, urine VEGF could be used to study the effect of such interventions in real-time in addition to being used as a predictor of BPD or ROP.

Acknowledgements

This effort was funded by NIH 2T32 HD07466-09, Pathobiology of Newborn and Developmental Diseases Training Grant (B.M.L.), 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources (L.A.K.), and NIH PO1HL67669-01, NIH Specialized Centers of Interdisciplinary Research, from the National Heart, Lung, and Blood Institute (D.E.I., L.J.V.M., and R.B.P.). The authors wish to thank the parents and babies who made this study possible.    We also would like to thank Lea Horwitz who assisted with data entry, as well as our nursing and medical colleagues who provided support and encouragement.

Disclosure Statement

The authors have no conflicts of interest to disclose.


Related Articles:

References

  1. Coalson JJ: Pathology of bronchopulmonary dysplasia. Semin Perinatol 2006;30:179-184.
    External Resources
  2. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al: Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443-456.
    External Resources
  3. Acarregui MJ, Penisten ST, Goss KL, Ramirez K, Snyder JM: Vascular endothelial growth factor gene expression in human fetal lung in vitro. Am J Respir Cell Mol Biol 1999;20:14-23.
    External Resources
  4. Lassus P, Turanlahti M, Heikkila P, Andersson LC, Nupponen I, Sarnesto A, et al: Pulmonary vascular 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;164:1981-1987.
    External Resources
  5. Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA, Maniscalco WM: Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;164:1971-1980.
    External Resources
  6. Asikainen TM, Chang LY, Coalson JJ, Schneider BK, Waleh NS, Ikegami M, et al: Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity. FASEB J 2006;20:1698-1700.
    External Resources
  7. Kunig AM, Balasubramaniam V, Markham NE, Morgan D, Montgomery G, Grover TR, et al: Recombinant human VEGF treatment enhances alveolarization after hyperoxic lung injury in neonatal rats. Am J Physiol Lung Cell Mol Physiol 2005;289:L529-L535.
    External Resources
  8. Thebaud B, Ladha F, Michelakis ED, Sawicka M, Thurston G, Eaton F, et al: Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation 2005;112:2477-2486.
    External Resources
  9. Smith LE: Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture. Invest Ophthalmol Vis Sci 2008;49:5177-5182.
    External Resources
  10. Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E: Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995;1:1024-1028.
    External Resources
  11. Mintz-Hittner HA, Kennedy KA, Chuang AZ: Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011;364:603-615.
    External Resources
  12. Sears JE, Hoppe G, Ebrahem Q, Anand-Apte B: Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy. Proc Natl Acad Sci USA 2008;105:19898-19903.
    External Resources
  13. Kronquist KE, Crandall BF, Tabsh KM: Characterization of fetal urinary proteins at midgestation and term. Biol Neonate 1984;46:267-275.
    External Resources
  14. Liu Y, Cox SR, Morita T, Kourembanas S: Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′′ enhancer. Circ Res 1995;77:638-643.
    External Resources
  15. Moore KA, Polte T, Huang S, Shi B, Alsberg E, Sunday ME, et al: Control of basement membrane remodeling and epithelial branching morphogenesis in embryonic lung by rho and cytoskeletal tension. Dev Dyn 2005;232:268-281.
    External Resources
  16. Wirtz HR, Dobbs LG: Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science 1990;250:1266-1269.
    External Resources
  17. Harding R, Hooper SB: Regulation of lung expansion and lung growth before birth. J Appl Physiol 1996;81:209-224.
    External Resources
  18. Bose CL, Dammann CE, Laughon MM: Bronchopulmonary dysplasia and inflammatory biomarkers in the premature neonate. Arch Dis Child Fetal Neonatal Ed 2008;93:F455-F461.
    External Resources
  19. Muratore CS, Nguyen HT, Ziegler MM, Wilson JM: Stretch-induced upregulation of VEGF gene expression in murine pulmonary culture: a role for angiogenesis in lung development. J Pediatr Surg 2000;35:906-913.
    External Resources
  20. Levesque BM, Mammoto A, Ingber D: Vascular endothelial growth factor is mechanically regulated in lung epithelial cells. Am J Respir Crit Care Med 2006;173:A2835.
  21. Hara A, Chapin CJ, Ertsey R, Kitterman JA: Changes in fetal lung distension alter expression of vascular endothelial growth factor and its isoforms in developing rat lung. Pediatr Res 2005;58:30-37.
    External Resources
  22. Bland RD, Mokres LM, Ertsey R, Jacobson BE, Jiang S, Rabinovitch M, et al: Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol 2007;293:L1099-L1110.
    External Resources
  23. Park JE, Keller GA, Ferrara N: The vascular endothelial growth factor isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound vascular endothelial growth factor. Mol Biol Cell 1993;4:1317-1326.
    External Resources
  24. Okamoto Y, Nagai T, Nakajo I, Seta K, Gotoh Y, Fujita N, et al: Determination of age-related changes in human vascular endothelial growth factor in the serum and urine of healthy subjects. Clin Lab 2008;54:173-177.
    External Resources

Author Contacts

Bernadette M. Levesque, MD

Division of Neonatology, St. Elizabeth's Medical Center

736 Cambridge Street, Quinn 207

Boston, MA 02135 (USA)

E-Mail Bernadette.levesque@childrens.harvard.edu

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: December 07, 2012
Accepted: March 26, 2013
Published online: May 24, 2013
Issue release date: July 2013

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 3

ISSN: 1661-7800 (Print)
eISSN: 1661-7819 (Online)

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References

  1. Coalson JJ: Pathology of bronchopulmonary dysplasia. Semin Perinatol 2006;30:179-184.
    External Resources
  2. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al: Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443-456.
    External Resources
  3. Acarregui MJ, Penisten ST, Goss KL, Ramirez K, Snyder JM: Vascular endothelial growth factor gene expression in human fetal lung in vitro. Am J Respir Cell Mol Biol 1999;20:14-23.
    External Resources
  4. Lassus P, Turanlahti M, Heikkila P, Andersson LC, Nupponen I, Sarnesto A, et al: Pulmonary vascular 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;164:1981-1987.
    External Resources
  5. Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA, Maniscalco WM: Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;164:1971-1980.
    External Resources
  6. Asikainen TM, Chang LY, Coalson JJ, Schneider BK, Waleh NS, Ikegami M, et al: Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity. FASEB J 2006;20:1698-1700.
    External Resources
  7. Kunig AM, Balasubramaniam V, Markham NE, Morgan D, Montgomery G, Grover TR, et al: Recombinant human VEGF treatment enhances alveolarization after hyperoxic lung injury in neonatal rats. Am J Physiol Lung Cell Mol Physiol 2005;289:L529-L535.
    External Resources
  8. Thebaud B, Ladha F, Michelakis ED, Sawicka M, Thurston G, Eaton F, et al: Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation 2005;112:2477-2486.
    External Resources
  9. Smith LE: Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture. Invest Ophthalmol Vis Sci 2008;49:5177-5182.
    External Resources
  10. Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E: Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995;1:1024-1028.
    External Resources
  11. Mintz-Hittner HA, Kennedy KA, Chuang AZ: Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011;364:603-615.
    External Resources
  12. Sears JE, Hoppe G, Ebrahem Q, Anand-Apte B: Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy. Proc Natl Acad Sci USA 2008;105:19898-19903.
    External Resources
  13. Kronquist KE, Crandall BF, Tabsh KM: Characterization of fetal urinary proteins at midgestation and term. Biol Neonate 1984;46:267-275.
    External Resources
  14. Liu Y, Cox SR, Morita T, Kourembanas S: Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′′ enhancer. Circ Res 1995;77:638-643.
    External Resources
  15. Moore KA, Polte T, Huang S, Shi B, Alsberg E, Sunday ME, et al: Control of basement membrane remodeling and epithelial branching morphogenesis in embryonic lung by rho and cytoskeletal tension. Dev Dyn 2005;232:268-281.
    External Resources
  16. Wirtz HR, Dobbs LG: Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science 1990;250:1266-1269.
    External Resources
  17. Harding R, Hooper SB: Regulation of lung expansion and lung growth before birth. J Appl Physiol 1996;81:209-224.
    External Resources
  18. Bose CL, Dammann CE, Laughon MM: Bronchopulmonary dysplasia and inflammatory biomarkers in the premature neonate. Arch Dis Child Fetal Neonatal Ed 2008;93:F455-F461.
    External Resources
  19. Muratore CS, Nguyen HT, Ziegler MM, Wilson JM: Stretch-induced upregulation of VEGF gene expression in murine pulmonary culture: a role for angiogenesis in lung development. J Pediatr Surg 2000;35:906-913.
    External Resources
  20. Levesque BM, Mammoto A, Ingber D: Vascular endothelial growth factor is mechanically regulated in lung epithelial cells. Am J Respir Crit Care Med 2006;173:A2835.
  21. Hara A, Chapin CJ, Ertsey R, Kitterman JA: Changes in fetal lung distension alter expression of vascular endothelial growth factor and its isoforms in developing rat lung. Pediatr Res 2005;58:30-37.
    External Resources
  22. Bland RD, Mokres LM, Ertsey R, Jacobson BE, Jiang S, Rabinovitch M, et al: Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol 2007;293:L1099-L1110.
    External Resources
  23. Park JE, Keller GA, Ferrara N: The vascular endothelial growth factor isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound vascular endothelial growth factor. Mol Biol Cell 1993;4:1317-1326.
    External Resources
  24. Okamoto Y, Nagai T, Nakajo I, Seta K, Gotoh Y, Fujita N, et al: Determination of age-related changes in human vascular endothelial growth factor in the serum and urine of healthy subjects. Clin Lab 2008;54:173-177.
    External Resources
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