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Am J Perinatol 2016; 33(05): 480-485
DOI: 10.1055/s-0035-1566294
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Vascular Endothelial Growth Factor/Placental Growth Factor Heterodimer Levels in Preterm Infants with Bronchopulmonary Dysplasia

Renato S. Procianoy
1   Department of Pediatrics, Universidade Federal do Rio Grande do Sul and Newborn Section, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil
,
Cláudia R. Hentges
1   Department of Pediatrics, Universidade Federal do Rio Grande do Sul and Newborn Section, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil
,
Rita C. Silveira
1   Department of Pediatrics, Universidade Federal do Rio Grande do Sul and Newborn Section, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil
› Author Affiliations
Further Information

Publication History

15 July 2015

30 September 2015

Publication Date:
03 November 2015 (online)

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Abstract

Background Bronchopulmonary dysplasia (BPD) is associated with changes in pulmonary angiogenesis. However, the role of the vascular endothelial growth factor/placental growth factor (VEGF/PlGF) heterodimer, an antiangiogenic factor, remains unknown in this disease.

Objective To compare VEGF/PlGF levels in preterm infants with and without BPD.

Methods This study was approved by the Institutional Review Board. Preterm neonates with birth weight <2,000 g and gestational age ≤34 weeks were included. Exclusion criteria were: neonates transferred from other institutions after 72 hours of life; death before blood collection; presence of major congenital malformations, inborn errors of metabolism, and early sepsis; and mothers with multiple pregnancies, TORCH infections, HIV infection, or autoimmune diseases. BPD was defined as the need for oxygen therapy for a period equal to or greater than 28 days, accompanied by radiographic changes compatible with the disease. Blood was collected from neonates in the first 72 hours of life. VEGF/PlGF levels were measured using the enzyme-linked immunosorbent assay method. The chi-square test, t-test, Mann–Whitney test, analysis of variance, and Kruskal–Wallis test were used for statistical analysis. Variables found to be significant in the univariate analysis were included in the multivariate analysis.

Results Seventy-three patients were included (19 with BPD, 43 without BPD, and 11 neonates who died in the first 28 days of life), with a mean (SD) gestational age of 30.32 (2.88) weeks and birth weight of 1,288 (462) g. Median VEGF/PlGF levels were higher in the groups with BPD and death in the first 28 days of life than in the group without BPD (16.46 [IQR, 12.19–44.57] and 20.64 [IQR, 13.39–50.22], respectively, vs. 9.14 [IQR, 0.02–20.64] pg/mL], p < 0.001). Higher VEGF/P1GF levels remained associated with BPD and death in the first 28 days of life in the multivariate analysis.

Conclusion Higher plasma VEGF/PlGF levels were found in preterm neonates with BPD and in those who died in the first 28 days of life, suggesting an important role of this substance in pulmonary vascular development.

Keywords

preterm neonates - VEGF/PlGF heterodimer - angiogenesis - respiratory distress syndrome - bronchopulmonary dysplasia
 

  • References

  • 1 Stroustrup A, Trasande L. Epidemiological characteristics and resource use in neonates with bronchopulmonary dysplasia: 1993-2006. Pediatrics 2010; 126 (2) 291-297
    CrossrefPubMedGoogle Scholar
  • 2 Meller S, Bhandari V. VEGF levels in humans and animal models with RDS and BPD: temporal relationships. Exp Lung Res 2012; 38 (4) 192-203
    CrossrefPubMedGoogle Scholar
  • 3 Thébaud B, Abman SH. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med 2007; 175 (10) 978-985
    CrossrefPubMedGoogle Scholar
  • 4 Thébaud B. Angiogenesis in lung development, injury and repair: implications for chronic lung disease of prematurity. Neonatology 2007; 91 (4) 291-297
    CrossrefPubMedGoogle Scholar
  • 5 Muy-Rivera M, Vadachkoria S, Woelk GB, Qiu C, Mahomed K, Williams MA. Maternal plasma VEGF, sVEGF-R1, and PlGF concentrations in preeclamptic and normotensive pregnant Zimbabwean women. Physiol Res 2005; 54 (6) 611-622
    PubMedGoogle Scholar
  • 6 Voelkel NF, Vandivier RW, Tuder RM. Vascular endothelial growth factor in the lung. Am J Physiol Lung Cell Mol Physiol 2006; 290 (2) L209-L221
    PubMedGoogle Scholar
  • 7 Tsao PN, Wei SC, Chou HC , et al. Vascular endothelial growth factor in preterm infants with respiratory distress syndrome. Pediatr Pulmonol 2005; 39 (5) 461-465
    CrossrefPubMedGoogle Scholar
  • 8 Yang WC, Chen CY, Chou HC, Hsieh WS, Tsao PN. Angiogenic factors in cord blood of preterm infants predicts subsequently developing bronchopulmonary dysplasia. Pediatr Neonatol 2015; doi:10.1016/j.pedneo.2015.02.001
    PubMedGoogle Scholar
  • 9 Ribatti D. The discovery of the placental growth factor and its role in angiogenesis: a historical review. Angiogenesis 2008; 11 (3) 215-221
    CrossrefPubMedGoogle Scholar
  • 10 Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med 2012; 2 (8) . doi:10.1101/cshperspect.a011056
    PubMedGoogle Scholar
  • 11 Tarallo V, Tudisco L, De Falco S. A placenta growth factor 2 variant acts as dominant negative of vascular endothelial growth factor A by heterodimerization mechanism. Am J Cancer Res 2011; 1 (2) 265-274
    PubMedGoogle Scholar
  • 12 Ballard JL, Khoury JC, Wedig K, Wang L, Eilers-Walsman BL, Lipp R. New Ballard Score, expanded to include extremely premature infants. J Pediatr 1991; 119 (3) 417-423
    CrossrefPubMedGoogle Scholar
  • 13 Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996; 87 (2) 163-168
    CrossrefPubMedGoogle Scholar
  • 14 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163 (7) 1723-1729
    CrossrefPubMedGoogle Scholar
  • 15 Hentges CR, Silveira RC, Ferreli RS, Procianoy RS. Influence of maternal pre-eclampsia on VEGF/PlGF heterodimer levels in preterm infants. J Matern Fetal Neonatal Med 2015; 28: 2166-2171
    CrossrefPubMedGoogle Scholar
  • 16 Ozkan H, Cetinkaya M, Koksal N. Increased incidence of bronchopulmonary dysplasia in preterm infants exposed to preeclampsia. J Matern Fetal Neonatal Med 2012; 25 (12) 2681-2685
    CrossrefPubMedGoogle Scholar
  • 17 Hansen AR, Barnés CM, Folkman J, McElrath TF. Maternal preeclampsia predicts the development of bronchopulmonary dysplasia. J Pediatr 2010; 156 (4) 532-536
    CrossrefPubMedGoogle Scholar
  • 18 Gien J, Kinsella JP. Pathogenesis and treatment of bronchopulmonary dysplasia. Curr Opin Pediatr 2011; 23 (3) 305-313
    Google Scholar
  • 19 Tang JR, Karumanchi SA, Seedorf G, Markham N, Abman SH. Excess soluble vascular endothelial growth factor receptor-1 in amniotic fluid impairs lung growth in rats: linking preeclampsia with bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2012; 302 (1) L36-L46
    CrossrefPubMedGoogle Scholar
  • 20 Furuya M, Kurasawa K, Nagahama K , et al. Disrupted balance of angiogenic and antiangiogenic signalings in preeclampsia. J Pregnancy 2011; 2011: 123717
    PubMedGoogle Scholar
  • 21 Hentges CR, Silveira RC, Procianoy RS. Angiogenic and antiangiogenic factors in preterm neonates born to mothers with and without preeclampsia. Am J Perinatol 2015;
    PubMedGoogle Scholar
  • 22 Briana DD, Malamitsi-Puchner A. Small for gestational age birth weight: impact on lung structure and function. Paediatr Respir Rev 2013; 14 (4) 256-262
    PubMedGoogle Scholar
  • 23 Shima Y, Kumasaka S, Migita M. Perinatal risk factors for adverse long-term pulmonary outcome in premature infants: comparison of different definitions of bronchopulmonary dysplasia/chronic lung disease. Pediatr Int 2013; 55 (5) 578-581
    CrossrefPubMedGoogle Scholar
  • 24 Eriksson A, Cao R, Pawliuk R , et al. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. Cancer Cell 2002; 1 (1) 99-108
    CrossrefPubMedGoogle Scholar
  • 25 Tarallo V, Vesci L, Capasso O , et al. A placental growth factor variant unable to recognize vascular endothelial growth factor (VEGF) receptor-1 inhibits VEGF-dependent tumor angiogenesis via heterodimerization. Cancer Res 2010; 70 (5) 1804-1813
    CrossrefPubMedGoogle Scholar
  • 26 Cho GJ, Roh GS, Kim HJ , et al. Differential expression of placenta growth factors and their receptors in the normal and pregnancy-induced hypertensive human placentas. J Korean Med Sci 2003; 18 (3) 402-408
    CrossrefPubMedGoogle Scholar
  • 27 Stefanini MO, Wu FTH, Mac Gabhann F, Popel AS. A compartment model of VEGF distribution in blood, healthy and diseased tissues. BMC Syst Biol 2008; 2: 77
    CrossrefPubMedGoogle Scholar
  • 28 DiSalvo J, Bayne ML, Conn G , et al. Purification and characterization of a naturally occurring vascular endothelial growth factor.placenta growth factor heterodimer. J Biol Chem 1995; 270 (13) 7717-7723
    CrossrefPubMedGoogle Scholar
  • 29 Cao Y, Chen H, Zhou L , et al. Heterodimers of placenta growth factor/vascular endothelial growth factor. Endothelial activity, tumor cell expression, and high affinity binding to Flk-1/KDR. J Biol Chem 1996; 271 (6) 3154-3162
    CrossrefPubMedGoogle Scholar
  • 30 De Falco S. The discovery of placenta growth factor and its biological activity. Exp Mol Med 2012; 44 (1) 1-9
    CrossrefPubMedGoogle Scholar
  • 31 Hadchouel A, Franco-Montoya ML, Delacourt C. Altered lung development in bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol 2014; 100 (3) 158-167
    CrossrefPubMedGoogle Scholar
  • 32 Walters EH, Reid D, Soltani A, Ward C. Angiogenesis: a potentially critical part of remodelling in chronic airway diseases?. Pharmacol Ther 2008; 118 (1) 128-137
    CrossrefPubMedGoogle Scholar
  • 33 Harkness LM, Kanabar V, Sharma HS, Westergren-Thorsson G, Larsson-Callerfelt AK. Pulmonary vascular changes in asthma and COPD. Pulm Pharmacol Ther 2014; 29 (2) 144-155
    CrossrefPubMedGoogle Scholar
  • 34 Harkness LM, Ashton AW, Burgess JK. Asthma is not only an airway disease, but also a vascular disease. Pharmacol Ther 2015; 148: 17-33
    CrossrefPubMedGoogle Scholar
  • 35 Pałgan K, Bartuzi Z. Angiogenesis in bronchial asthma. Int J Immunopathol Pharmacol 2015; 28 (3) 415-420
    PubMedGoogle Scholar
  • 36 Sow FB, Gallup JM, Meyerholz DK, Ackermann MR. Gene profiling studies in the neonatal ovine lung show enhancing effects of VEGF on the immune response. Dev Comp Immunol 2009; 33 (6) 761-771
    CrossrefPubMedGoogle Scholar
  • 37 Olivier AK, Gallup JM, van Geelen A, Ackermann MR. Exogenous administration of vascular endothelial growth factor prior to human respiratory syncytial virus a2 infection reduces pulmonary pathology in neonatal lambs and alters epithelial innate immune responses. Exp Lung Res 2011; 37 (3) 131-143
    CrossrefPubMedGoogle Scholar