Endothelin-A receptor blockade prevents and partially reverses neonatal hypoxic pulmonary vascular remodeling.
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 (ET(A)) receptor activation, mediates hypoxic pulmonary vasoconstriction. Our objectives were to develop a newborn mouse model of HPVR and to test the hypothesis that ET(A) 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 (ET(A) 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 mum 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 ET(A) blockade. These results indicate that ET-1, acting via ET(A) 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.
Ambalavanan
Namasivayam
N
Department of Pediatrics, University of Alabama at Burmingham, Alabama 35233, USA. ambal@uab.edu
Bulger
Arlene
A
Murphy-Ullrich
Joanne
J
Oparil
Suzanne
S
Chen
Yiu-Fai
YF
D000818:Animals; D000831:Animals, Newborn; D003369:Cottonseed Oil / Q000494:pharmacology; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D000860:Hypoxia; D007231:Infant, Newborn; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology*; D011652:Pulmonary Circulation / Q000187:drug effects; D013997:Time Factors
D003369:Cottonseed Oil; D065130:Endothelin A Receptor Antagonists; D009842:Oligopeptides; C087220:BQ 610; D010100:Oxygen