Placental Adaptation to Early-Onset Hypoxic Pregnancy and Mitochondria-Targeted Antioxidant Therapy in a Rodent Model

Abstract

The placenta responds to adverse environmental conditions by adapting its capacity for substrate transfer to maintain fetal growth and development. Early-onset hypoxia effects on placental morphology and activation of the unfolded protein response (UPR) were determined using an established rat model in which fetal growth restriction is minimized. We further established whether maternal treatment with a mitochondria-targeted antioxidant (MitoQ) confers protection during hypoxic pregnancy. Wistar dams were exposed to normoxia (21% O2) or hypoxia (13% to 14% O2) from days 6 to 20 of pregnancy with and without MitoQ treatment (500 μmol/L in drinking water). On day 20, animals were euthanized and weighed, and the placentas from male fetuses were processed for stereology to assess morphology. UPR activation in additional cohorts of frozen placentas was determined with Western blot analysis. Neither hypoxic pregnancy nor MitoQ treatment affected fetal growth. Hypoxia increased placental volume and the fetal capillary surface area and induced mitochondrial stress as well as the UPR, as evidenced by glucose-regulated protein 78 and activating transcription factor (ATF) 4 protein up-regulation. MitoQ treatment in hypoxic pregnancy increased placental maternal blood space surface area and volume and prevented the activation of mitochondrial stress and the ATF4 pathway. The data suggest that mitochondria-targeted antioxidants may be beneficial in complicated pregnancy via mechanisms protecting against placental stress and enhancing placental perfusion.

Hyperandrogenism and insulin resistance‐induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome

“…), further studies are needed to investigate new tools, such as the mitochondria‐targeted antioxidant MitoQ (Nuzzo et al . ), for manipulating ROS levels as a way to improve pregnancy outcomes for women with PCOS.…”

Placental mitochondria adapt developmentally and in response to hypoxia to support fetal growth

“…The contribution of O 2 consumption by non-OXPHOS-related processes (such as steroid and nitric oxide production) could also be explored in future work using ETS inhibitors (e.g., rotenone and antimycin). Indeed, studies using the mitochondrial-targeted antioxidant MitoQ suggest non-OXPHOS processes may have a significant effect on substrate exchange, placental secretions, and fetal growth in hypoxic rat dams (17,43).…”

“…In humans, hypoxia is the main cause of fetal growth restriction at high altitude and is a common feature of pregnancy complications at sea level (13). In pregnant rodents and guinea pigs, inhalation hypoxia adapts placental morphology and nutrient transport to the fetus dependent upon the degree, timing, and length of O 2 restriction ( [14][15][16][17][18][19]. Changes in placental mitochondrial function are also seen in compromised human pregnancies (3) and in nutritionally induced fetal growth restriction in rodents, in association with changes in mitochondrial function and biogenesis (20,21).…”

Preeclampsia link to gestational hypoxia

“…These include an increase in placental weight, vascularization and capillary surface area for exchange, which depend on the severity and duration of the hypoxic insult and may not necessarily lead to significant effects on fetal body weight. [73][74][75][76][77] In this context, studies in rodent pregnancy by our own laboratory have shown that late-onset hypoxia for the last third of gestation leads to significant FGR. 78 In contrast, earlyonset hypoxic pregnancy increases placental weight, cushioning the adverse effects on fetal development, leading to maintained birth weight.…”