Abstract
Vascular endothelial growth factor (VEGF) is a potent mitogen with angiogenic and vasoactive properties. VEGF can bind to two types of receptors. VEGF receptor 2 (VEGFR2) is mainly responsible for the dilator response to VEGF through nitric oxide (NO) release, whereas VEGFR1 may sequestrate the ligand. We hypothesized that in neonatal hypoxia-induced pulmonary hypertension, VEGF vasodilation is reduced. The dilator response to VEGF was assessed in isolated perfused lung of 1-d-old piglets that were exposed to either normoxia or hypoxia (fraction of inspired oxygen 0.10) for 14 d. The plasma and pulmonary artery concentration of VEGF was measured by quantitative sandwich enzyme immunoassay in piglets that were exposed to either normoxia or hypoxia for 1, 3, 7, or 14 d. The expression of VEGFR1, VEGFR2, and endothelial NO synthase in pulmonary artery was measured in the same study groups using Western blot analysis. VEGF (10−12–10−9 M) induces a dose-dependent relaxation in 14-d normoxic piglets, whereas vasodilation is abolished after 14 d of hypoxia. VEGF tissue concentration is increased by hypoxia. VEGFR1 expression is dramatically increased after 1, 3, and 7 d of hypoxia compared with normoxia and returns to normal afterward. VEGFR2 expression is reduced by hypoxia at 14 d. However, endothelial NO synthase expression is not affected by hypoxia compared with normoxia. In neonatal hypoxia-induced pulmonary hypertension, VEGF is increased, whereas vasodilation to VEGF is abolished. This reduced vasodilation may be due to decreased VEGFR2 expression. We speculate that sequestration by VEGFR1 may also limit, to some extent, the vascular protecting effect of VEGF, thus contributing to the pathophysiologic changes seen in neonatal hypoxia-induced pulmonary hypertension.
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Abbreviations
- eNOS:
-
endothelial nitric oxide synthase
- Fio2:
-
fraction of inspired oxygen
- iNOS:
-
inducible nitric oxide synthase
- LV+S:
-
left ventricle plus septum
- NO:
-
nitric oxide
- PECAM:
-
platelet endothelial cell adhesion molecule
- PPHN:
-
persistent pulmonary hypertension of the newborn
- RV:
-
right ventricle
- VEGF:
-
vascular endothelial growth factor
- VEGFR:
-
vascular endothelial growth factor receptor
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This work was supported by the Canadian Institutes of Health Research (53137).
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Nadeau, S., Baribeau, J., Janvier, A. et al. Changes in Expression of Vascular Endothelial Growth Factor and Its Receptors in Neonatal Hypoxia-Induced Pulmonary Hypertension. Pediatr Res 58, 199–205 (2005). https://doi.org/10.1203/01.PDR.0000169969.18669.D2
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DOI: https://doi.org/10.1203/01.PDR.0000169969.18669.D2
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