Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore, School of Medicine, 655 W. Baltimore St., Baltimore, MD, 21201, USA.
Reprod Sci. 2023 Oct;30(10):2996-3009. doi: 10.1007/s43032-023-01245-5. Epub 2023 May 3.
Chronic intrauterine hypoxia is a significant pregnancy complication impacting fetal heart growth, metabolism, and mitochondrial function, contributing to cardiovascular programming of the offspring. PGC1α (peroxisome proliferator-activated receptor γ co-activator 1α) is the master regulator of mitochondrial biogenesis. We investigated the effects of hypoxia on PGC1α expression following exposure at different gestational ages. Time-mated pregnant guinea pigs were exposed to normoxia (NMX, 21% O) or hypoxia (HPX, 10.5% O) at either 25-day (early-onset) or 50-day (late-onset) gestation, and all fetuses were extracted at term (term = ~65-day gestation). Expression of nuclear PGC1α, sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and mitochondrial sirtuin 3 (SIRT3) was measured, along with SIRT3 activity and mitochondrial acetylation of heart ventricles of male and female fetuses. Early-onset hypoxia increased (P<0.05) fetal cardiac nuclear PGC1α and had no effect on mitochondrial acetylation of either growth-restricted males or females. Late-onset hypoxia had either no effect or decreased (P<0.05) PCC1α expression in males and females, respectively, but increased (P<0.05) mitochondrial acetylation in both sexes. Hypoxia had variable effects on expression of SIRT1, AMPK, SIRT3, and SIRT3 activity depending on the sex. The capacity of the fetal heart to respond to hypoxia differs depending on the gestational age of exposure and sex of the fetus. Further, the effects of late-onset hypoxia on fetal heart function impose a greater risk to male than female fetuses, which has implications toward cardiovascular programming effects of the offspring.
慢性宫内缺氧是一种严重的妊娠并发症，会影响胎儿心脏的生长、代谢和线粒体功能，导致后代心血管发育编程。PGC1α（过氧化物酶体增殖物激活受体γ共激活因子 1α）是线粒体生物发生的主要调节因子。我们研究了在不同胎龄暴露于缺氧时对 PGC1α 表达的影响。将时间匹配的怀孕豚鼠暴露于常氧（NMX，21% O）或缺氧（HPX，10.5% O）中，分别在 25 天（早期发病）或 50 天（晚期发病）胎龄，所有胎儿均在足月（足月=~65 天妊娠）提取。测量了雄性和雌性胎儿心脏心室的核 PGC1α、SIRT1（沉默调节蛋白 1）、AMP 激活的蛋白激酶（AMPK）和线粒体 SIRT3（沉默调节蛋白 3）的表达，以及 SIRT3 活性和线粒体乙酰化。早期发病的缺氧增加了（P<0.05）胎儿心脏核 PGC1α，对生长受限的雄性或雌性的线粒体乙酰化没有影响。晚期发病的缺氧对雄性和雌性的 PCC1α 表达分别没有影响或降低（P<0.05），但都增加了（P<0.05）两性的线粒体乙酰化。缺氧对 SIRT1、AMPK、SIRT3 和 SIRT3 活性的表达有不同的影响，取决于性别。胎儿心脏对缺氧的反应能力取决于暴露的胎龄和胎儿的性别。此外，晚期发病的缺氧对胎儿心脏功能的影响对雄性胎儿的风险大于雌性胎儿，这对后代心血管发育编程的影响具有重要意义。
