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Impaired lung vascular endothelial growth factor in extremely premature baboons developing bronchopulmonary
Francis Tambunting1, Kay D A Beharry, Joshua Waltzman
1Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of California, Irvine Medical Center, Orange, CA 92868, USA.
Insights
Impaired vascular endothelial growth factor (VEGF) and VEGF receptor expression in premature baboons may cause bronchopulmonary dysplasia (BPD) by disrupting lung development. This study investigated VEGF ontogeny in baboon lungs and its alteration by oxygen exposure.
Area of Science:
- Neonatal physiology
- Pulmonary medicine
- Developmental biology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants exposed to oxygen and mechanical ventilation.
- BPD pathogenesis involves abnormal lung microvasculature and alveolar development.
- Impaired vascular endothelial growth factor (VEGF) and its receptor expression may underlie BPD/CLD.
Purpose of the Study:
- To investigate the developmental expression of VEGF and its receptors in baboon lungs.
- To determine if oxygen exposure and mechanical ventilation alter these developmental patterns.
Main Methods:
- Examined lung specimens from baboons at various gestational ages (125-185 days).
- Analyzed lungs from control groups and three oxygen-exposed groups with varying prematurity and oxygen levels.
- Quantified messenger RNA (mRNA) expression of VEGF splice variants and receptors.
Main Results:
- VEGF189 was the predominant splice variant throughout lung development.
- Elevated VEGF121 mRNA was observed in premature baboons with BPD/CLD.
- Suppressed mRNA for VEGF189, VEGF165, and key VEGF receptors (Flt-1, KDR/Flk-1, neuropilin 1) was noted in BPD models.
Conclusions:
- Reduced expression of VEGF and its receptor mRNA in premature baboons with BPD/CLD may contribute to lung vascular and alveolar abnormalities.
- VEGF signaling pathways are critical in lung development and may be disrupted in BPD.
- Findings suggest potential targets for therapeutic intervention in BPD.
Background:
Preterm infants exposed to O2 with mechanical ventilation often develop bronchopulmonary dysplasia (BPD), a form of chronic lung disease (CLD). The pathogenesis of BPD/CLD involves dysmorphic microvasculature and disrupted alveolarization. This may be due to impaired vascular endothelial growth factor (VEGF) and VEGF receptor expression.
Methods:
To examine the ontogeny of VEGF and VEGF receptors in baboon lungs from 125 to 185 (term) days gestation and to determine whether exposure to O2 and mechanical ventilation alter these ontogenic profiles, we examined lung specimens from three O2-exposed groups: (1) animals delivered at 125 days gestation and exposed to O2 for 14 days as needed; (2) animals delivered at 140 days gestation and exposed to O2 for 10 days as needed; and (3) animals delivered at 140 days gestation and exposed to 100% O2 for 10 days. Lungs from gestational age-matched controls were also examined at 125, 140, 160, 175, and 185 (term) days.
Results:
VEGF189 was the most abundant splice variant in the lungs at all stages of development. Extremely premature baboons developing BPD/CLD had higher lung VEGF121 messenger ribonucleic acid (mRNA) expression. However, transcripts for VEGF189, VEGF165, and VEGF receptors (Fms-like tyrosine kinase-1 [Flt-1], kinase-insert domain receptor [KDR]/fetal liver kinase-1 [Flk-1], and neuropilin 1) were suppressed in the BPD models.
Conclusions:
We conclude that impaired VEGF and VEGF receptor mRNA expression in lungs from extremely premature baboons developing BPD/CLD may contribute to dysmorphic microvasculature and disrupted alveolarization.