Endothelin and the regulation of uterine and placental perfusion in hypoxia-induced fetal growth restriction.
OBJECTIVE
Normal placental function is dependent on maintenance of uteroplacental perfusion. Endothelin, a potent vasoconstrictor, is produced in and is active in the uteroplacental vasculature. The purpose of this study was to determine the role of endothelin in the regulation of uteroplacental perfusion under normal conditions, and in hypoxia-induced fetal growth restriction.


METHODS
Timed-pregnant Sprague-Dawley rats, outfitted with arterial catheters, were maintained in either a normoxic or a normobaric hypoxic (12% oxygen) atmosphere from day 18 to 21 of gestation. During this time, the endothelin receptor A antagonist, A-127722, or its vehicle was administered. Regional blood flow was determined on gestational day 21 using 57Co-labeled microspheres. Data were analyzed by analysis of variance with statistical significance accepted at P<.05.


RESULTS
Both placental and uterine placental bed perfusion were significantly decreased by hypoxia and returned to normal values with the endothelin antagonist (P<.01 and P<.05, respectively). Fetal weights were significantly lower in the hypoxic group (P<.001) and restored to control levels by the antagonist.


CONCLUSIONS
In the rat, endothelin contributes little to the regulation of uteroplacental perfusion under normal conditions. Hypoxia results in a decrease in perfusion of the uteroplacental bed and of the placenta, and perfusion in both of these beds is normalized by endothelin A receptor antagonism. We conclude that endothelin plays a primary role in the pathophysiology of hypoxia-induced fetal growth restriction by reducing uteroplacental perfusion.
Thaete
Larry G
LG
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. lthaete@enh.org
Dewey
Elizabeth R
ER
Neerhof
Mark G
MG
D000818:Animals; D000077868:Atrasentan; D001783:Blood Flow Velocity; D001794:Blood Pressure; D003037:Cobalt Radioisotopes; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology* / Q000503:physiopathology*; D005311:Fetal Hypoxia / Q000150:complications*; D005333:Fetus / Q000098:blood supply; D005865:Gestational Age; D007668:Kidney / Q000098:blood supply; D008863:Microspheres; D010100:Oxygen / Q000008:administration & dosage; D010920:Placenta / Q000098:blood supply*; D011247:Pregnancy; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014599:Uterus / Q000098:blood supply*
D003037:Cobalt Radioisotopes; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D010100:Oxygen; D000077868:Atrasentan