Angiogenic Factors in Bronchopulmonary Dysplasia

Tremendous progress in neonatal intensive care and surfactant replacement therapy has dramatically improved the survival rate of premature infants suffering from respiratory distress syndrome.1Tsou K.I. Tsao P.N. Taiwan Infant Development Collaborative Study GroupThe morbidity and survival of very-low-birth-weight infants in Taiwan.Acta Paediatr Taiwan. 2003; 44: 349-355PubMed Google Scholar The risk of the development of bronchopulmonary dysplasia (BPD), however, remains high in premature infants.2Su B.H. Hsieh W.S. Hsu C.H. Chang J.H. Lien R. Lin C.H. et al.Neonatal outcomes of extremely preterm infants from Taiwan: comparison with Canada, Japan, and the USA.Pediatr Neonatol. 2015; 56: 46-52Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Although BPD was known as postnatal injury from oxygen and mechanical ventilation therapy in premature infants, it is now recognized as a result of antenatal and perinatal factors that interrupt lung development in extremely premature infants. The causes of aberrant lung development have been studied widely. Research revealed that angiogenesis is needed for adequate pulmonary vascular development that could support normal alveolar lung growth. Vascular endothelial growth factor (VEGF), a potent angiogenic factor, was decreased in the lungs of preterm infants with fatal BPD.3Bhatt A.J. Amin S.B. Chess P.R. Watkins R.H. Maniscalco W.M. Expression of vascular endothelial growth factor and Flk-1 in developing and glucocorticoid-treated mouse lung.Pediatr Res. 2000; 47: 606-613Crossref PubMed Scopus (99) Google Scholar Placenta growth factor (PlGF) is a 45- to 50-kDa dimeric glycoprotein. It has been found in placenta, endothelial cells, epithelial cells, and various tumor types. Because of its high homology with VEGF, it was classified as a member of the VEGF family of growth factors. VEGF stimulates angiogenesis by stimulating the VEGF tyrosine kinase receptor-2 (VEGFR-2), whereas PlGF potentiates the angiogenic response to VEGF via stimulation of VEGFR-1.4Carmeliet P. Moons L. Luttun A. Vincenti V. Compernolle V. De Mol M. 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: 575-583Crossref PubMed Scopus (1403) Google Scholar In contrast to the role of VEGF in physiological and pathological angiogenesis, the role of PlGF is limited to pathological conditions, such as inflammation, ischemia, and cancer.4Carmeliet P. Moons L. Luttun A. Vincenti V. Compernolle V. De Mol M. 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: 575-583Crossref PubMed Scopus (1403) Google Scholar Soluble fms-like tyrosine kinase-1, also known as VEGF receptor-1 (sFlt-1 or sVEGFR-1), is a tyrosine kinase protein that disables proteins that cause blood vessel growth. It binds and reduces free circulating levels of the proangiogenic factors VEGF and PlGF.5Kendall R.L. Wang G. Thomas K.A. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR.Biochem Biophys Res Commun. 1996; 226: 324-328Crossref PubMed Scopus (628) Google Scholar Pro- and antiangiogenic factors have been studied regarding involvement in pathologic lung development. As shown in the study of proangiogenic and antiangiogenic factors in cord blood from premature infants with and without BPD, PlGF, but not VEGF or sFlt-1, was higher in the BPD group than the non-BPD group.6Yang W.C. Chen C.Y. Chou H.C. Hsieh W.S. Tsao P.N. Angiogenic factors in cord blood of preterm infants predicts subsequently developing bronchopulmonary dysplasia.Pediatr Neonatol. 2015; 56: 382-385Abstract Full Text Full Text PDF Scopus (15) Google Scholar This proangiogenic factor may be an effective biomarker because it has the capability to be detected in the early phase, or even before BPD has developed, to avoid or diminish the injurious effects of BPD. The limitation of this biomarker is that its concentration can be biased by an inflammatory status in other parts of the body, because this is not lung specific. In fact, this biomarker is neither universally accepted nor used routinely in the clinical setting. The serum proangiogenic factor PlGF followed a bell-shaped curve with advancing gestational age, in which the concentration increased during the first two trimesters and decreased as pregnancy progressed to term in normal pregnancy women7Levine R.J. Maynard S.E. Qian C. Lim K.H. England L.J. Yu K.F. et al.Circulating angiogenic factors and the risk of preeclampsia.N Engl J Med. 2004; 350: 672-683Crossref PubMed Scopus (2870) Google Scholar; whether this trend is found in the cord blood of premature newborns requires a further large cohort study for clarification. Furthermore, lower PlGF level was found in women in whom preeclampsia developed than in normal pregnancy, even prior to clinical presentation. By contrast, PlGF level was higher in cord blood from infants with BPD. In view of this, a population-based large cohort study of very-low-birth-weight Taiwanese infants was reviewed, and BPD occurred significantly less frequently in the infants born to mothers with preeclampsia.8Yen T.A. Yang H.I. Hsieh W.S. Chou H.C. Chen C.Y. Tsou K.I. et al.Preeclampsia and the risk of bronchopulmonary dysplasia in VLBW infants: a population based study.PloS One. 2013; 8: e75168Crossref PubMed Scopus (50) Google Scholar BPD is a complicated multisystem disease. In the neonatal period, it exhibits as severe respiratory distress, with a significant effect on the quality of life of affected infants. Even as infants grow, despite an improvement in their general health, airflow limitation persists, lung function declines, growth is slower, and cognitive ability is decreased.9Carraro S. Filippone M. Da Dalt L. Ferraro V. Maretti M. Bressan S. et al.Bronchopulmonary dysplasia: the earliest and perhaps the longest lasting obstructive lung disease in humans.Early Hum Dev. 2013; 89: S3-5Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 10Wang P.W. Fang L.J. Tsou K.I. Taiwan Infant Developmental Collaborative Study Group The growth of very-low-birth-weight infants at 5 years old in Taiwan.Pediatr Neonatol. 2014; 55: 114-119Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Currently, there is no specific or effective treatment for BPD. Vitamin A, diuretics, caffeine, bronchodilators, stem cells, etc. are the treatment choices. In addition, the angiogenic factor was shown to enhance lung structure in a rat model, but whether it has any potential implication for the treatment of BPD requires further research. The author declares no conflicts of interest.

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