Abstract
Hypoxia-induced pulmonary vascular remodeling (HPVR) may lead to persistent pulmonary hypertension of the newborn or cor pulmonale. Endothelin-1 (ET-1), via endothelin-A (ETA) receptor activation, mediates hypoxic pulmonary vasoconstriction. Our objectives were to develop a newborn mouse model of HPVR and to test the hypothesis that ETA blockade would prevent and reverse HPVR in this model. C57BL/6 mice (n = 64) were exposed to 12% oxygen (HYP group) or room air (RA group) from birth to 2 wk of age. The mice were injected intraperitoneally daily with either BQ-610 (ETA blocker) or vehicle (cottonseed oil) from birth (prevention study) or from 6 d of age (reversal study). HPVR was assessed histologically by pulmonary vascular morphometry by an examiner masked to study group, and by measurement of the right ventricle to left ventricle (RV/LV) thickness ratio. Hypoxia increased medial wall thickness (%WT) in pulmonary arteries <100 μm in diameter and RV/LV thickness ratio. BQ-610 prevented the hypoxia-induced increase in %WT and RV/LV thickness ratio when given from birth, and later therapy partially reversed the hypoxia-induced increase in %WT but not RV/LV thickness ratio. These data show that in the newborn mouse model, chronic hypoxia leads to HPVR that can be completely prevented and partially reversed by ETA blockade. These results indicate that ET-1, acting via ETA receptors, is a mechanism of pathophysiologic significance underlying neonatal HPVR. Development of this newborn mouse model of HPVR facilitates investigation of mechanisms underlying this important and severe disease entity in human infants.
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Abbreviations
- ET-1:
-
endothelin-1
- ETA:
-
endothelin-A receptor
- HPVR:
-
hypoxia-induced pulmonary vascular remodeling
- PPHN:
-
persistent pulmonary hypertension of the newborn
- %WT:
-
percentage wall thickness of tunica media as compared to external diameter
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Funded in part by National Heart, Lung, and Blood Institute Grants HL-44195, HL-50147, HL-45990, HL-07457, HL-56046; National Institute of Child Health and Human Development grant K08 HD046513; and a Child Health Research Center Grant through NICHHD P30HD28831.
Presented in part at the meeting of the Pediatric Academic Societies' Annual Meeting, Seattle, WA, 2003.
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Ambalavanan, N., Bulger, A., Murphy-Ullrich, J. et al. Endothelin-A Receptor Blockade Prevents and Partially Reverses Neonatal Hypoxic Pulmonary Vascular Remodeling. Pediatr Res 57, 631–636 (2005). https://doi.org/10.1203/01.PDR.0000159512.55862.69
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DOI: https://doi.org/10.1203/01.PDR.0000159512.55862.69
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