Endothelin-1 mediates hypoxia-induced increases in vascular collagen in the newborn mouse lung.
Endothelin-1 (ET-1) mediates hypoxia-mediated pulmonary vascular remodeling (HPVR), and endothelin-A receptor (ET-AR) blockade prevents HPVR in newborn mice. Our objective was to determine postnatal effects of chronic hypoxia and/or ET-AR blockade on lung ET-1, ET-AR, ET-BR, and vascular collagen and elastin. Newborn C57BL/6 mice (n = 6-8/gp) given either BQ610 (ET-AR blocker) or vehicle were exposed to air or hypoxia (12% O2) from birth for 1, 3, or 14 d. Lung ET-1 was assessed by ELISA, and ET-AR and ET-BR by immunohistochemistry. Vascular collagen and elastin were assessed by quantitative image analysis. ET-1, ET-AR, ET-BR, collagen I and III, and tropoelastin mRNA levels were assessed by real-time quantitative RT-PCR. We observed that: 1) hypoxia attenuated the normal postnatal decrease in ET-1 and collagen content; 2) ET-AR blockade reduced collagen independent of O2; 3) hypoxia increased elastin mRNA expression and attenuated the normal postnatal decrease in elastin content; and 4) BQ610 reduced elastin mRNA but not elastin content. We conclude that, in neonatal mice, hypoxia attenuates normal postnatal decreases in ET-1, vascular collagen, and elastin. ET-AR blockade reduces collagen fiber area but not mRNA, and does not decrease elastin despite reducing its expression.
Ambalavanan
Namasivayam
N
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA. ambal@uab.edu
Li
Peng
P
Bulger
Arlene
A
Murphy-Ullrich
Joanne
J
Oparil
Suzanne
S
Chen
Yiu-Fai
YF
D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism*; D004549:Elastin / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000860:Hypoxia; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011247:Pregnancy; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C087220:BQ 610; D003094:Collagen; D004549:Elastin; D010100:Oxygen