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1 Pediatric Heart Lung Center and Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: grover.theresa{at}tchden.org.
We have previously shown that lung vascular endothelial growth factor (VEGF)expression is decreased in a fetal lamb model of PPHN, and that VEGF165 inhibiton causes severe pulmonary hypertension in fetal lambs. Therefore, we hypothesized that treatment with rhVEGF165 would preserve endothelium-dependent vasodilation and reduce the severity of pulmonary vascular remodeling in an experimental model of PPHN. We studied the effects of daily intrapulmonary infusions of rhVEGF after partial ligation of the ductus arteriosus (DA). We performed surgery in 24 late gestation fetal lambs, and placed catheters in the main pulmonary artery, left atrium, and aorta for pressure measurements, and in the left pulmonary artery for drug infusions. A pressure transducer was placed around the LPA to measure blood flow to the left lung (Qp), and the DA surgically constricted to induce pulmonary hypertension. rhVEGF165 (5 or 50 ugm/day) or vehicle was infused for 7 or 14 days. Acetylcholine or 8-bromo-cGMP were infused on days 2 and 13 to assess endothelium-dependent and independent vasodilation, respectively. Acetylcholine-induced vasodilation was reduced in PPHN lambs after 14 days (change in Qp from baseline, 106% vs. 11%; p<0.05). In contrast, the response to acetylcholine was preserved in lambs treated with rhVEGF (change in Qp, 94% vs. 90%). Pulmonary vasodilation to 8-Br-cGMP was not altered in PPHN lambs or enhanced by VEGF treatment. rhVEGF treatment increased expression of lung eNOS protein (p<0.05), and decreased pulmonary artery wall thickness by 34% (p<0.001) vs. PPHN lambs. We conclude that VEGF165 preserves endothelium-dependent vasodilation, upregulates eNOS expression, and reduces the severity of pulmonary vascular remodeling in experimental PPHN.
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