Abstract
Pregnancy complications associated with chronic fetal hypoxia have been linked to the development of adult cardiovascular disease in the offspring. Prenatal hypoxia has been shown to increase placental oxidative stress and impair placental function in a sex-specific manner, thereby affecting fetal development. As oxidative stress is central to placental dysfunction, we developed a placenta-targeted treatment strategy using the antioxidant MitoQ encapsulated into nanoparticles (nMitoQ) to reduce placental oxidative/nitrosative stress and improve placental function without direct drug exposure to the fetus in order to avoid off-target effects during development. We hypothesized that, in a rat model of prenatal hypoxia, nMitoQ prevents hypoxia-induced placental oxidative/nitrosative stress, promotes angiogenesis, improves placental morphology, and ultimately improves fetal oxygenation. Additionally, we assessed whether there were sex differences in the effectiveness of nMitoQ treatment. Pregnant rats were intravenously injected with saline or nMitoQ (100 μl of 125 μM) on gestational day (GD) 15 and exposed to either normoxia (21% O2) or hypoxia (11% O2) from GD15 to 21. On GD21, placentae from both sexes were collected for detection of superoxide, nitrotyrosine, nitric oxide, CD31 (endothelial cell marker), and fetal blood spaces, Vegfa and Igf2 mRNA expression in the placental labyrinth zone. Prenatal hypoxia decreased male fetal weight, which was not changed by nMitoQ treatment; however, placental efficiency (fetal/placental weight ratio) decreased by hypoxia and was increased by nMitoQ in both males and females. nMitoQ treatment reduced the prenatal hypoxia-induced increase in placental superoxide levels in both male and female placentae but improved oxygenation in only female placentae. Nitrotyrosine levels were increased in hypoxic female placentae and were reduced by nMitoQ. Prenatal hypoxia reduced placental Vegfa and Igf2 expression in both sexes, while nMitoQ increased Vegfa and Igf2 expression only in hypoxic female placentae. In summary, our study suggests that nMitoQ treatment could be pursued as a potential preventative strategy against placental oxidative stress and programming of adult cardiovascular disease in offspring exposed to hypoxia in utero. However, sex differences need to be taken into account when developing therapeutic strategies to improve fetal development in complicated pregnancies, as nMitoQ treatment was more effective in placentae from females than males.
Highlights
Chronic fetal hypoxia, a common consequence of pregnancy complications, has been linked to the development of cardiovascular and metabolic diseases in the adult offspring
Prenatal hypoxia had no effect on fetal weight or abdominal girth but increased placental weight, which was significantly reduced by Nanoparticle Encapsulated MitoQ (nMitoQ) treatment (Table 3). nMitoQ treatment had no effect on female fetal weight or abdominal girth (Table 3)
We found that prenatal hypoxia reduced fetal and maternal blood space area in placentae from only male offspring (Figures 4A,B). nMitoQ did not change fetal and maternal blood space area in placentae from males (Figure 4A); in female offspring, nMitoQ treatment increased fetal blood space area in placentae exposed to prenatal hypoxia (Figures 4C,D)
Summary
A common consequence of pregnancy complications (e.g., placental insufficiency), has been linked to the development of cardiovascular and metabolic diseases in the adult offspring. One impact of excessive superoxide anions is the resultant scavenging of nitric oxide (NO) to produce RNS (e.g., peroxynitrite; Myatt and Cui, 2004); increased superoxide levels could reduce NO bioavailability and impair the important contribution of NO in feto-placental angiogenesis (Webster et al, 2008). The placental response to oxidative stress appears to be different in placentae from males compared with females (reviewed in Rosenfeld, 2015). Human studies have shown that the placental oxidative stress response to adverse maternal environments (such as oxidative/nitrosative stress and reduced levels of antioxidants) in general appears to be more pronounced in male versus female placentae (Stark et al, 2011; Sedlmeier et al, 2014; Muralimanoharan et al, 2015; Evans and Myatt, 2017). Examining sex-specific differences in the placental responses to adverse maternal environments or placental phenotypes as an outcome of the adverse environments is warranted
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