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Articles in PresS, published online ahead of print November 22, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00135.2002
Submitted on May 9, 2002
Accepted on November 8, 2002
1 Pediatric Heart Lung Center and Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: grover.theresa{at}tchden.org.
Although vascular endothelial growth factor (VEGF) plays a vital role in lung vascular growth in the embryo, its role in maintaining endothelial function and modulating vascular structure during late fetal life has not been studied. We hypothesized that impaired lung VEGF signaling causes pulmonary hypertension, endothelial dysfunction, and structural remodeling prior to birth. To determine whether lung VEGF expression is decreased in an experimental model of PPHN, we measured lung VEGF and VEGF-R protein content from fetal lambs 7-10 days after ductus arteriosus ligation (132-140 days gestation; term=147 days). In contrast with the surge in lung VEGF expression during late gestation in controls (p<0.001), chronic intrauterine pulmonary hypertension reduced lung VEGF expression by 78% (p<0.05). To determine whether VEGF inhibition during late gestation causes pulmonary hypertension, we treated fetal lambs with EYE001, an aptamer that specifically inhibits VEGF165. In comparison with vehicle controls, EYE001 treatment elevated pulmonary artery pressure and PVR by 22% and 50%, respectively (p<0.005), caused RVH (p<0.05), and increased wall thickness of small pulmonary arteries (p<0.005). EYE001 treatment reduced lung eNOS protein content by 50% (p<0.05 vs. control), and preferentially impaired the pulmonary vasodilator response to acetylcholine, an endothelium-dependent agent. We conclude that chronic intrauterine pulmonary hypertension markedly decreases lung VEGF expression, and that selective inhibition of VEGF165 mimics the structural and physiologic changes of experimental PPHN. We speculate that hypertension downregulates VEGF expression in the developoing lung, and that impaired VEGF signaling may contribute to the pathogenesis of PPHN.
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