Effect of Chronic Hypoxia on PKC-Mediated Thin Filament Signaling Pathway in Uterine Arteries During Pregnancy.

Abstract

Chronic hypoxia during pregnancy has profound effects on uterine artery contractility and attenuates the pregnancy-induced increase in uterine blood flow, which is associated with an increased risk of preeclampsia and fetal intrauterine growth restriction. Given that PKC plays a key role in regulating myogenic tone of resistance-sized uterine arteries via a thin filament mechanism of actin polymerization, the present study tests the hypothesis that chronic hypoxia upregulates PKC-mediated actin polymerization resulting in increased uterine vascular contractility during pregnancy. Fourth branches of the main uterine arteries were isolated from nonpregnant (NPUA) and pregnant (PUA) (~140 days gestation) sheep maintained at either sea-level or high altitude (3,820 m for 110 days, PaO2: 60 mmHg), and contractions were measured in the organ bath. In the sea-level normoxic animals, the PKC activator PDBu-induced contractions were significantly decreased in PUA, as compared with NPUA. Pretreatment with an actin polymerization inhibitor cytochalasin B significantly decreased the PDBu-induced contractions in both NPUA and PUA, and eliminated the difference between them. Long-term high altitude hypoxia selectively increased the PDBu-induced contractions in PUA, but not in NPUA. The hypoxia-mediated enhanced contractions in PUA were restored by cytochalasin B. In addition, cytochalasin B slightly, but significantly inhibited norepinephrine-induced contractions of both NPUA and PUA. In contrast to the findings of PKC-mediated contractions, neither pregnancy nor chronic hypoxia affected the inhibitory effect of cytochalasin B on the norepinephrine-induced contractions. These findings suggest that pregnancy selectively attenuates PKC-mediated actin polymerization and myogenic contractions of the uterine arteries. This adaptation of pregnancy is inhibited by chronic hypoxia, which is likely to contribute to aberrant uteroplacental circulation and pregnancy complications caused by chronic hypoxia during gestation.