Babies that experience low oxygen levels in the womb due to pregnancy complications often go on to develop heart disease in adulthood.
A study using sheep has discovered that a specialised antioxidant called MitoQ can prevent heart disease at its very onset.
The results are published today in the journal Science Advances.
Genetics, and their interaction with lifestyle risk factors such as smoking and obesity, play a role in determining heart disease risk in adults.
But there is also strong evidence that the environment experienced during sensitive periods of fetal development directly influences long-term cardiovascular health – a process known as ‘developmental programming.’
Low oxygen in the womb – known as chronic fetal hypoxia – is one of the most common complications in human pregnancy.
In a process termed ‘oxidative stress,’ low oxygen to the developing fetus can cause damage to its heart and blood vessels. Fetal hypoxia can be diagnosed when a scan during pregnancy shows the baby is not growing properly.
“Many people may be predisposed to heart disease as adults because of the low level of oxygen they received in the womb.
By providing a specific mitochondria-targeted antioxidant supplement to mothers whose pregnancy is complicated by fetal hypoxia, we can potentially prevent this,” said Professor Dino Giussani from the University of Cambridge’s Department of Physiology, Development and Neuroscience, who led the study.
Chronic hypoxia is common to many complications of pregnancy.
It can be caused by a number of conditions including pre-eclampsia, infection of the placenta, gestational diabetes or maternal obesity.
Oxidative stress largely originates in the cells’ mitochondria – the ‘batteries’ that power our cells – where the processes of respiration and energy production occur.
To target mitochondria the Cambridge team used MitoQ, developed by Professor Mike Murphy and his colleagues at the University of Cambridge’s MRC-Mitochondrial Biology Unit.
MitoQ selectively accumulates within mitochondria, where it works to reduce oxidative stress.
Having established the safety of the treatment, the researchers gave MitoQ to pregnant sheep under low oxygen conditions.
They found that the mitochondrial therapy protects against fetal growth restriction and high blood pressure in the offspring as adults. Using chicken embryos they also showed that MitoQ protects against mitochondria-derived oxidative stress.
MitoQ has already been used in a number of human trials, for example it was shown to lower hypertension in older subjects.
It is very exciting to see the potential to use MitoQ to treat a baby during a problematic pregnancy and prevent problems arising far later in life.
There’s still a long way to go before this can be used by pregnant mothers, but our work points to new possibilities for novel treatments,” said Professor Murphy, who was also involved in the study.
This is the first time that MitoQ has been tested during sheep pregnancy. Sheep are animals whose cardiovascular development resembles that of a human baby more closely than laboratory rats and mice. Chicken embryos were also used to isolate the direct effects of MitoQ therapy on the embryonic heart independent of any influence on the mother or placenta.
“Our cardiovascular health is influenced by the lifestyle choices we make in adult life, but can also be traced back to the conditions we experienced when developing inside the womb,” said Professor James Leiper, Associate Medical Director at the British Heart Foundation.
He added: “This study reveals a plausible way to reduce the future risk of high blood pressure and consequent heart disease in babies from complicated pregnancies.
Further research is now needed to translate these findings from animals to humans and identify the most effective time in development to give the MitoQ supplement to ‘at risk’ babies – whether that’s a particular point during pregnancy or soon after birth. Overcoming this next hurdle will enable it to be tested in clinical trials.”
Cardiovascular disease is a group of disorders of the heart and blood vessels that can cause heart attacks and strokes. It claims the life of one in three people, and costs the United States and Canada US$130 billion and the United Kingdom over £30 billion every year. The majority of these costs are for treatments that improve outcomes, but do not cure the disease.
There are increasing calls within the public health community to change the focus of cardiovascular disease research from treatment to prevention. By looking at the specific circumstances that increase the risk of developing heart disease, interventions can be made as early as possible rather than waiting until disease has become irreversible.
“If we want to reduce the prevalence of cardiovascular disease, we need to think of prevention rather than a cure.
Applying this concept to pregnancy complications, we can bring preventative medicine all the way back into the womb – it’s treatment before birth. It completely changes our way of thinking about heart disease,” said Giussani.
Prenatal Oxidative Stress
Prenatal hypoxia is a condition responsible for the disease and fetal death or newborn . The placenta is an organ important for communication between the pregnant woman and the fetus.
The proper functioning of this organ is important for fetal development. Hypoxia is defined as a decrease in O2 necessary for the physiological functions of tissue .
An increase of ROS levels, generated from an incomplete reduction of O2, is one of the most common mechanisms induced to hypoxia. Normally the placenta produces reactive oxygen species (ROS) such as superoxide anion (O2−), hydroxyl radical (HO−) and hydrogen peroxide (H2O2) .
These molecules are highly unstable and possess a strong chemical reactivity due to the presence of unpaired electrons in the external orbital . Due to this instability, ROS are inclined to yield or acquire an electron from other electrically unstable molecules, in order to achieve a stable energy state.
In this way their lead a series of redox reactions that are important for the survival cellular. Normal ROS production is ensured by a balance between the production of these molecules and the antioxidant defense system.
The main antioxidant system is provided to the activity of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT).
Non-enzymatic antioxidants such as thiols (e.g., glutathione, GSH), protein thiols; vitamins A, B6, B12, C and E; selenium; folic acid; and the β-carotenoids, bilirubin and uric acid, represent another defense mechanism able to reduce the excessive ROS production .
During pregnancy, normal ROS levels can be involved in trophoblast proliferation and differentiation and in the modulation of the vascular responses of the placenta . However, an increase in ROS levels is responsible for placental functional changes.
Following fetal hypoxia, low levels of O2 lead to a reduction in the activity of the mitochondrial electron transport chain.
Thereby, this reduction promoting an increase in the percentage of O2 incompletely reduced with consequent production of ROS, such as O2− [20,23]. The mitochondrial electron transport chain represents a major ROS producer.
Another source of ROS is represented by NADPH oxidase, responsible for the endogenous production of O2− . In the vascular endothelium, cytochrome P450 is another enzyme responsible for the production of OH− and O2− .
The metalloflavoprotein xanthine oxidase is another enzyme that following the oxidation of hypoxanthine to xanthine and uric acid, leads to the production of O2− . In the placenta, in hypoxic conditions, the mitochondrial oxygen consumption is downregulated.
This leads to a reduction in the reserves of high energy phosphates generating high levels of xanthine, hypoxanthine, NADH, FADH, hydrogen ions (H+) and lactic acid .
Hypoxia induces a decrease in the enzymatic activity of the pumps of ATP-asi dependent membranes, reduction of the membrane potential and an increase in the flow of cytosolic calcium (Ca2+) levels.
In hypoxic conditions, the increase in intracellular Ca2+, due to the activation of voltage-dependent channels and release by the mitochondria and the endoplasmic reticulum, establishes a loop that triggers the mechanism of apoptosis and neuronal necrosis .
Especially in the neuronal cells, the entry of Ca2+ favors the accumulation of glutamate. Glutamate, interacting with N-methyl-D aspartate (NMDA) receptors, intensifies the intracellular current of Ca2+, further contributing to neuronal damage .
Moreover, Ca2+ is responsible for activating nitric oxide synthase (NOS), involved in the production of nitric oxide (NO). Among the three known NOS isoforms, endothelial nitric oxide synthase (eNOS) is a Ca2+-dependent flavoenzyme that generates NO .
In this process Ca2+ plays an important role in the activation of eNOS, regulating the binding of eNOS with calmodulin  NO is a powerful endothelial vasodilator involved in the regulation of vascular tone, in the control of blood flow in the tissues and in the aggregation of platelets.
In the placental, NO plays a key role in vasodilatation of the uteroplacental arteries, an important mechanism that determines the invasion of the trophoblasts and the remodeling of the endothelium . Therefore, the altered balance of NO and ROS play a critical role in modulating the umbilical-placental vascular function in different prenatal conditions.
Therefore, high levels of ROS are responsible for damage to several cellular components such as DNA, proteins and lipids with consequent impairment of normal cellular functions .
During pregnancy, within 10–12 weeks of gestation, there is an increase in the flow of maternal blood into the placenta, which leads to a local increase in oxygen and consequently an increase in the activity of antioxidant enzymes.
However, an excessive increase in ROS that cannot be countered by the antioxidant response, induce oxidative stress conditions. In the placenta oxidative stress, especially in this stage of pregnancy, is responsible for reducing the invasion of trophoblasts.
This cascade of events induces different conditions that can be linked to alterations of fetal development and in serious cases even to early pregnancy failure [34,35].
The brain is more sensitive to changes in O2 levels. Oxidative stress is the main factor that induces neuronal cell death in the immature brain .
During embryogenesis, hypoxic damage also delays neuronal migration and alters the expression of numerous neurotransmitters [37,38]. These mechanisms increase the risk of neural birth defects, brain damage and long-term cognitive impairment in learning and memory [39,40]. Moreover, it can also predispose offspring to the future onset of epileptic conditions .
New Antioxidant Treatments for Prenatal Hypoxia
Complications of pregnancy such as fetal hypoxia activate physiological survival processes such as ROS production; therefore, clinical strategies such as the use of antioxidants can be helpful in managing fetal problems as well as long-term consequences on offspring (Table 2).
Synthesis of the studies aimed at testing the antioxidant properties of some substances such as melatonin, vitamin C, resveratrol, nMitoQ, hydrogen and erythropoietin. Specifically, the table shows the animal models used in the studies and the type of hypoxic damage induced. Additionally, the type of treatment, the dosage, the route of administration and the therapeutic effects obtained are described.
|Antioxidant Treatments||Animal Models||Hypoxic Damage||Treatment||Dosage||Route of Administration||Therapeutic Effects||Ref.|
|MELATONIN||Pregnant Wistar rats||Occlusion of the uterine artery for 20 min;|
(1 h prior to fetal hypoxia)
|10 mg/kg||Intraperitoneal injections||Reduction of ROS|||
|VITAMIN C||Pregnant Wistar rats||Hypoxic conditions (13% O2);|
(every day during pregnancy)
|5 mg/mL||Drinking water||Prevention of oxidative damage; improvement of placental function and protection fetal|
|RESVERATROL||Pregnant Sprague Dawley rats||Hypoxic conditions (11% O2);|
(for 9 weeks)
|4 g/kg||Diet integration||Promotion of cardiac recovery by increasing cardiac SOD.|||
(for 18 weeks)
|Reduce heart damage by increasing in cardiac p-AMPK and SOD2 levels.|||
|nMITOQ||Pregnant Sprague Dawley rats||Hypoxic conditions (11% O2);|
|125 μM||Intravenous injections||Restoration of molecular changes induced by fetal hypoxia such as microRNA, bone morphogenetic protein and amino acids|
and reduction of oxidative stress in the placenta.
|Improvement of the sensitivity to vasorelaxation and the systolic dysfunction in the offspring of 7 and 13 months and reduction of placental oxidative stress.|||
|Improvement of the oxygenation, angiogenesis and placental morphology, especially in the placenta of female offspring.|||
|HYDROGEN||Pregnant Sprague Dawley rats||Hypoxic conditions (8% O2% and 92% N2);|
(4 h of exposure to this condition at GD 17–1 at the term)
|Mixture of hydrogen (2% H2, 8% O2% and 90% N2)||–||Restoration of the anomalies of sensory responses and prevent neurological damage induced by fetal hypoxia.|||
|ERYTHROPOIETIN||Pregnant Sprague Dawley rats||Occlusion of the uterine artery for 60 min;|
(After 4 days from the fetal hypoxia per 5 days; PD 1–5)
|500 U/kg per 1 day, 1000 U/kg per 3 days and 2000 U/kg per 5 days.||Intraperitoneal injections||Improvement of the neurological damage and the correct development of the nervous system.|||
|2000 U/kg||Reduction of the excessive activity of the calpain and protection of the central nervous system.|||
Okatani Y. et al. studied the effects of melatonin in improving the oxidative stress damage induced by ischemia/reperfusion of mitochondria in the rat placenta.
Melatonin is an important scavenger secreted by the pineal gland that showed broad antioxidant, anti-inflammatory and antiapoptotic effects.
The results showed that the administration of melatonin induced an increase in the markers of mitochondrial activity and a decrease in the concentration of reactive substances with thiobarbituric acid. Therefore, exogenous melatonin exhibited an antioxidant action and could be useful as a treatment for and fetal hypoxia .
Vitamin C is another antioxidant that may be used as a possible therapeutic treatment during fetal hypoxia. Vitamin C in mammals is one of the most important endogenous antioxidants.
Richter H.G. et al. showed that maternal treatment with vitamin C prevented placental oxidative stress associated with maternal exposure to hypoxia .
Fetal hypoxia makes the offspring susceptible to the development of metabolic and cardiovascular disorders . Resveratrol is a natural polyphenol that carries out its cardio-protective effects reducing ROS production, through the activation of molecules such as Adenosine Monophosphate Kinase Cardiac (AMPK) and the up-regulation of antioxidant enzymes such as SOD in endothelial cells of the arteries and smooth muscle cells [60,61].
Shah A. et al. evaluated the beneficial action of resveratrol in preventing alterations of metabolism and cardiac dysfunctions. The study showed that at 12 months of age, fetal hypoxia and the fatty acid diet have induced metabolic alteration in offspring, especially in male offspring.
Resveratrol treatment has proven effective in preventing cardiovascular disease, probably through increasing cardiac SOD . However, as in the previous study , even after 21 weeks, resveratrol treatment promotes an improvement in diastolic function and increases the ability to recover after an ischemia/reperfusion injury.
The cardiovascular beneficial effects of resveratrol can be explained with a significant increase of the cardiac p-AMPK protein levels. Therefore, resveratrol could be a therapeutic opportunity used to counteract also the long-term oxidative damage induced by fetal hypoxia .
The use of mitochondrial antioxidants, such as MitoQ, could prevent the secretion of factors that cause DNA damage. Tom J. Phillips et al. assessed the ability of MitoQ to prevent DNA damage mediated by the release of harmful particles from the placenta induced following prenatal hypoxia.
In order to prevent MitoQ from crossing the placenta, MitoQ was bonded with nanoparticles (nMitoQ), which accumulate in bilayered trophoblast barrier and do not cross through it, as previously demonstrated [64,65].
Administration of nMitoQQ appears to normalize alterations of microRNA, bone morphogenetic proteins and amino acids in placental secretions and plasma is capable of preventing molecular changes induced by fetal hypoxia, reducing oxidative stress in the placenta .
The same research team also evaluated the effects of placental treatment with nMitoQ in reducing the risk of developing cardiovascular disease in offspring exposed to prenatal hypoxia.
The results of the study showed that hypoxia-induced changes in heart function that occurred following adulthood were attenuated by treatment with nMitoQ . Additionally, the administration of nMitoQ reduced the O2− levels in both the placenta and the fetus and the nitrotyrosine levels in the placenta.
In this way, nMitoQ reduces the oxidative stress levels, highlighting that the efficacy of the treatment is targeted to the placenta. Moreover, treatment with nMitoQ resulted in an increase of vascular endothelial growth factor A (VEGFA) and insulin-like growth factor 2 (IGF-2).
In conclusion, nMitoQ, reducing oxidative stress, improves oxygenation, angiogenesis and placental morphology, especially in the placenta of female offspring .
During the first week after birth, negative geotropism is important, both for rats and mice, to develop a sense of adaptation to the environment; just as straightening reflex is a neuromuscular response aimed at bringing the body into the normal vertical position [69,70].
Liu W. et al. observed that offspring subjected to hypoxic damage showed an alteration of these sensory responses. However, treatment with hydrogen during pregnancy restoring the anomalies of sensory responses and therefore preventing neurological damage induced by hypoxia .
Fetal hypoxia is also responsible for the alteration of neurological development and consequent cognitive delays, behavioral deficits, cerebral paralysis and other complications . The erythropoietin shows neuroprotective properties  through several mechanisms of action including the reduction of oxidative stress  and damage induced by NO .
In this regard, Mazur M. et al. have proven that the administration of neonatal endogenous erythropoietin, 4 days later to hypoxic damage, has promoted the survival of oligodendrocytes and neurons.
Additionally, improving histological damage was also observed, even after 24 days of treatment. In conclusion, erythropoietin improved the neurological insult induced by hypoxia and allow the correct development of the nervous system .
In view of these findings, Jantzi L.L. et al. assessed the effects of erythropoietin on calpain activated following fetal hypoxia. Calpain is a protein involved in cellular homeostasis during the development of the central nervous system and in the degradation of proteins in the mature central nervous system.
Therefore, its alteration may be responsible for the cognitive delay . The hypoxic damage induced high calpain activity postnatal in the cortex. The erythropoietin treatment reduced cortical calpain activity and promoted positive modulation of markers of neurological development, such as neuronal potassium-chloride co-transporter (KCC2), Myelin Basic Protein (MBP) and phosphorylated-neurofilament (p-NF). Thereby, erythropoietin can be valid therapeutic tools aimed at protecting the offspring from possible alterations in the development of the central nervous system .
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278841/
More information: “Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction” Science Advances (2020). advances.sciencemag.org/lookup … 1126/sciadv.eabb1929