04 February 2019

Insulin-like growth factor-1 promotes angiogenesis, prevents pulmonary hypertension and preserves lung growth in experimental models of bronchopulmonary dysplasia


Antenatal factors, such as chorioamnionitis and preeclampsia, are strongly associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. Whether IGF-1 treatment can prevent BPD is unknown.


To evaluate whether postnatal IGF-1 treatment of newborn rats with recombinant human (rh)IGF-1/rhIGFBP-3 improves lung vascular and alveolar growth and prevents PH in 2 models of BPD induced by chorioamnionitis or preeclampsia.


Endotoxin (10 μg/sac) or sFlt-1 (1 μg/sac) was administered into the amniotic sac of pregnant rats at 20 days gestation (E20) as models of chorioamnionitis and preeclampsia, respectively. Pups were delivered by c-section at E22 and treated with rhIGF-1/rhIGFBP-3 (0.2 - 20 mg/kg/day, intraperitoneal) or buffer for 2 weeks. Study endpoints included radial alveolar counts (RAC), vessel density, and right ventricular hypertrophy (RVH) by the weight ratio (right ventricle/left ventricle+septum x 100). In addition, the effects of IGF-1 (250 ng/ml) on fetal pulmonary artery endothelial cell (PAEC) growth and tube formation was studied by standard methods in vitro.


When compared with controls, antenatal endotoxin reduced RAC and increased RVH by 42% and 72% in 2-week rats, respectively (p<0.01 for each). In the preeclampsia model, antenatal sFlt-1 reduced RAC and increased RVH by 32% and 46%, respectively (p<0.01 for each). For both models, postnatal rhIGF-1/rhIGFBP-3 treatment restored RAC to normal values and prevented RVH at all study doses when compared with placebo injections. IGF-1 stimulated growth, tube formation and upregulated VEGF and eNOS expression in fetal PAEC.


Postnatal rhIGF-1/rhIGFBP-3 treatment preserved lung structure and prevented RVH in two antenatal models of BPD and enhanced angiogenic signaling in fetal PAEC. We speculate that rhIGF-1/rhIGFBP-3 treatment may provide a novel strategy for the prevention of BPD and PH, especially as associated with chorioamnionitis or preeclampsia


Key Contributors

Gregory Seedorf , Christina Kim, Erica Mandell, Douglas Shepherd, Steven Abman. From, the Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045 USA.

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