title: Excess soluble vascular endothelial growth factor receptor-1 in amniotic fluid impairs lung growth in rats: linking preeclampsia with bronchopulmonary dysplasia.
abstract: Epidemiological studies have shown that maternal preeclampsia (PE) increases the risk of bronchopulmonary dysplasia (BPD), but the underlying mechanism is unknown. Soluble vascular endothelial growth factor receptor-1 (soluble VEGFR1, known as soluble fms-like tyrosine kinase 1, or sFlt-1), an endogenous antagonist of vascular endothelial growth factor (VEGF), is markedly elevated in amniotic fluid and maternal blood in PE. Therefore, we hypothesized that antenatal exposure to excess sFlt-1 disrupts lung development through impaired VEGF signaling in utero, providing a mechanistic link between PE and BPD. To determine whether increased sFlt-1 in amniotic fluid is sufficient to cause sustained abnormalities of lung structure during infancy, sFlt-1 or saline was injected into amniotic sacs of pregnant Sprague-Dawley rats at 20 days of gestation (term, 22 days). After birth, pups were observed through 14 days of age for study. We found that intra-amniotic sFlt-1 treatment decreased alveolar number, reduced pulmonary vessel density, and caused right and left ventricular hypertrophy in 14-day-old rats. In addition, intra-amniotic sFlt-1 treatment suppressed activation of lung VEGF receptor-2 and increased apoptosis in endothelial and mesenchymal cells in the newborn lung. We conclude that exposure to excess sFlt-1 in amniotic fluid during late gestation causes sustained reductions in alveolarization and pulmonary vascular growth during infancy, accompanied by biventricular hypertrophy suggesting pulmonary and systemic hypertension. We speculate that impaired VEGF signaling in utero due to exposure of high amniotic fluid levels of sFlt-1 in PE disrupts lung growth and contributes to the increased risk of BPD in infants born to mothers with PE.
authors: Pediatric Heart Lung Center, Dept. of Pediatrics, Univ. of Colorado Health Sciences Center, P15-4460A, Mail Stop 8614, 12700 East 19th Ave., Aurora, CO 80045, USA. Jen-Ruey.Tang@ucdenver.edu
authors: Jen-Ruey
authors: JR
authors: Tang
authors: S Ananth
authors: SA
authors: Karumanchi
authors: Gregory
authors: G
authors: Seedorf
authors: Neil
authors: N
authors: Markham
authors: Steven H
authors: SH
authors: Abman
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects; D000653:Amniotic Fluid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001997:Bronchopulmonary Dysplasia / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000503:physiopathology; D007231:Infant, Newborn; D008168:Lung / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D038081:Organogenesis / Q000187:drug effects*; D011225:Pre-Eclampsia / Q000503:physiopathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000008:administration & dosage*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2