Mitochondrial Dysfunction in Endothelial Progenitor Cells: Unraveling Insights from Vascular Endothelial Cells.

Endothelial dysfunction is associated with several lifestyle-related diseases, including cardiovascular and neurodegenerative diseases, and it contributes significantly to the global health burden. Recent research indicates a link between cardiovascular risk factors (CVRFs), excessive production of reactive oxygen species (ROS), mitochondrial impairment, and endothelial dysfunction. Circulating endothelial progenitor cells (EPCs) are recruited into the vessel wall to maintain appropriate endothelial function, repair, and angiogenesis. After attachment, EPCs differentiate into mature endothelial cells (ECs). Like ECs, EPCs are also susceptible to CVRFs, including metabolic dysfunction and chronic inflammation. Therefore, mitochondrial dysfunction of EPCs may have long-term effects on the function of the mature ECs into which EPCs differentiate, particularly in the presence of endothelial damage. However, a link between CVRFs and impaired mitochondrial function in EPCs has hardly been investigated. In this review, we aim to consolidate existing knowledge on the development of mitochondrial and endothelial dysfunction in the vascular endothelium, place it in the context of recent studies investigating the consequences of CVRFs on EPCs, and discuss the role of mitochondrial dysfunction. Thus, we aim to gain a comprehensive understanding of mechanisms involved in EPC deterioration in relation to CVRFs and address potential therapeutic interventions targeting mitochondrial health to promote endothelial function.

Nurturing through Nutrition: Exploring the Role of Antioxidants in Maternal Diet during Pregnancy to Mitigate Developmental Programming of Chronic Diseases.

Chronic diseases represent one of the major causes of death worldwide. It has been suggested that pregnancy-related conditions, such as gestational diabetes mellitus (GDM), maternal obesity (MO), and intra-uterine growth restriction (IUGR) induce an adverse intrauterine environment, increasing the offspring's predisposition to chronic diseases later in life. Research has suggested that mitochondrial function and oxidative stress may play a role in the developmental programming of chronic diseases. Having this in mind, in this review, we include evidence that mitochondrial dysfunction and oxidative stress are mechanisms by which GDM, MO, and IUGR program the offspring to chronic diseases. In this specific context, we explore the promising advantages of maternal antioxidant supplementation using compounds such as resveratrol, curcumin, N-acetylcysteine (NAC), and Mitoquinone (MitoQ) in addressing the metabolic dysfunction and oxidative stress associated with GDM, MO, and IUGR in fetoplacental and offspring metabolic health. This approach holds potential to mitigate developmental programming-related risk of chronic diseases, serving as a probable intervention for disease prevention.

Characterizing Early Cardiac Metabolic Programming via 30% Maternal Nutrient Reduction during Fetal Development in a Non-Human Primate Model.

Intra-uterine growth restriction (IUGR) is a common cause of fetal/neonatal morbidity and mortality and is associated with increased offspring predisposition for cardiovascular disease (CVD) development. Mitochondria are essential organelles in maintaining cardiac function, and thus, fetal cardiac mitochondria could be responsive to the IUGR environment. In this study, we investigated whether in utero fetal cardiac mitochondrial programming can be detectable in an early stage of IUGR pregnancy. Using a well-established nonhuman IUGR primate model, we induced IUGR by reducing by 30% the maternal diet (MNR), both in males (MNR-M) and in female (MNR-F) fetuses. Fetal cardiac left ventricle (LV) tissue and blood were collected at 90 days of gestation (0.5 gestation, 0.5 G). Blood biochemical parameters were determined and heart LV mitochondrial biology assessed. MNR fetus biochemical blood parameters confirm an early fetal response to MNR. In addition, we show that in utero cardiac mitochondrial MNR adaptations are already detectable at this early stage, in a sex-divergent way. MNR induced alterations in the cardiac gene expression of oxidative phosphorylation (OXPHOS) subunits (mostly for complex-I, III, and ATP synthase), along with increased protein content for complex-I, -III, and -IV subunits only for MNR-M in comparison with male controls, highlight the fetal cardiac sex-divergent response to MNR. At this fetal stage, no major alterations were detected in mitochondrial DNA copy number nor markers for oxidative stress. This study shows that in 90-day nonhuman primate fetuses, a 30% decrease in maternal nutrition generated early in utero adaptations in fetal blood biochemical parameters and sex-specific alterations in cardiac left ventricle gene and protein expression profiles, affecting predominantly OXPHOS subunits. Since the OXPHOS system is determinant for energy production in mitochondria, our findings suggest that these early IUGR-induced mitochondrial adaptations play a role in offspring's mitochondrial dysfunction and can increase predisposition to CVD in a sex-specific way.

Metabolic mitochondrial alterations prevail in the female rat heart 8 weeks after exercise cessation.

BACKGROUND: The consumption of high-caloric diets strongly contributes to the development of non-communicable diseases (NCDs), including cardiovascular disease, the leading cause of mortality worldwide. Exercise (along with diet intervention) is one of the primary non-pharmacological approaches to promote a healthier lifestyle and counteract the rampant prevalence of NCDs. The present study evaluated the effects of exercise cessation after a short period training on the cardiac metabolic and mitochondrial function of female rats. METHODS: Seven-week-old female Sprague-Dawley rats were fed a control or a high-fat, high-sugar (HFHS) diet and, after 7 weeks, the animals were kept on a sedentary lifestyle or submitted to endurance exercise for 3 weeks (6 days per week, 20-60 min/day). The cardiac samples were analysed 8 weeks after exercise cessation. RESULTS: The consumption of the HFHS diet triggered impaired glucose tolerance, whereas the HFHS diet and physical exercise resulted in different responses in plasma adiponectin and leptin levels. Cardiac mitochondrial respiration efficiency was decreased by the HFHS diet consumption, which led to reduced ATP and increased NAD(P)H mitochondrial levels, which remained prevented by exercise 8 weeks after cessation. Exercise training-induced cardiac adaptations in redox balance, namely increased relative expression of Nrf2 and downstream antioxidant enzymes persist after an eight-week exercise cessation period. CONCLUSIONS: Endurance exercise modulated cardiac redox balance and mitochondrial efficiency in female rats fed a HFHS diet. These findings suggest that exercise may elicit cardiac adaptations crucial for its role as a non-pharmacological intervention for individuals at risk of developing NCDs.

Maternal hepatic adaptations during obese pregnancy encompass lobe-specific mitochondrial alterations and oxidative stress.

Maternal obesity (MO) is rising worldwide, affecting half of all gestations, constituting a possible risk-factor for some pregnancy-associated liver diseases (PALD) and hepatic diseases. PALD occur in approximately 3% of pregnancies and are characterized by maternal hepatic oxidative stress (OS) and mitochondrial dysfunction. Maternal hepatic disease increases maternal and fetal morbidity and mortality. Understanding the role of MO on liver function and pathophysiology could be crucial for better understanding the altered pathways leading to PALD and liver disease, possibly paving the way to prevention and adequate management of disease. We investigated specific hepatic metabolic alterations in mitochondria and oxidative stress during MO at late-gestation. Maternal hepatic tissue was collected at 90% gestation in Control and MO ewes (fed 150% of recommended nutrition starting 60 days before conception). Maternal hepatic redox state, mitochondrial respiratory chain (MRC), and OS markers were investigated. MO decreased MRC complex-II activity and its subunits SDHA and SDHB protein expression, increased complex-I and complex-IV activities despite reduced complex-IV subunit mtCO1 protein expression, and increased ATP synthase ATP5A subunit. Hepatic MO-metabolic remodeling was characterized by decreased adenine nucleotide translocator 1 and 2 (ANT-1/2) and voltage-dependent anion channel (VDAC) protein expression and protein kinase A (PKA) activity (P<0.01), and augmented NAD+/NADH ratio due to reduced NADH levels (P<0.01). MO showed an altered redox state with increased OS, increased lipid peroxidation (P<0.01), decreased GSH/GSSG ratio (P=0.005), increased superoxide dismutase (P=0.03) and decreased catalase (P=0.03) antioxidant enzymatic activities, lower catalase, glutathione peroxidase (GPX)-4 and glutathione reductase protein expression (P<0.05), and increased GPX-1 abundance (P=0.03). MO-related hepatic changes were more evident in the right lobe, corroborated by the integrative data analysis. Hepatic tissue from obese pregnant ewes showed alterations in the redox state, consistent with OS and MRC and metabolism remodeling. These are hallmarks of PALD and hepatic disease, supporting MO as a risk-factor and highlighting OS and mitochondrial dysfunction as mechanisms responsible for liver disease predisposition.

Fetoplacental endothelial dysfunction in gestational diabetes mellitus and maternal obesity: A potential threat for programming cardiovascular disease.

Gestational diabetes mellitus (GDM) and maternal obesity (MO) increase the risk of adverse fetal outcomes, and the incidence of cardiovascular disease later in life. Extensive research has been conducted to elucidate the underlying mechanisms by which GDM and MO program the offspring to disease. This review focuses on the role of fetoplacental endothelial dysfunction in programming the offspring for cardiovascular disease in GDM and MO pregnancies. We discuss how pre-existing maternal health conditions can lead to vascular dysfunction in the fetoplacental unit and the fetus. We also examine the role of fetoplacental endothelial dysfunction in impairing fetal cardiovascular system development and the involvement of nitric oxide and hydrogen sulfide in mediating fetoplacental vascular dysfunction. Furthermore, we suggest that the L-Arginine-Nitric Oxide and the Adenosine-L-Arginine-Nitric Oxide (ALANO) signaling pathways are pertinent targets for research. Despite significant progress in this area, there are still knowledge gaps that need to be addressed in future research.

Made in the Womb: Maternal Programming of Offspring Cardiovascular Function by an Obesogenic Womb.

Obesity incidence has been increasing at an alarming rate, especially in women of reproductive age. It is estimated that 50% of pregnancies occur in overweight or obese women. It has been described that maternal obesity (MO) predisposes the offspring to an increased risk of developing many chronic diseases in an early stage of life, including obesity, type 2 diabetes, and cardiovascular disease (CVD). CVD is the main cause of death worldwide among men and women, and it is manifested in a sex-divergent way. Maternal nutrition and MO during gestation could prompt CVD development in the offspring through adaptations of the offspring's cardiovascular system in the womb, including cardiac epigenetic and persistent metabolic programming of signaling pathways and modulation of mitochondrial metabolic function. Currently, despite diet supplementation, effective therapeutical solutions to prevent the deleterious cardiac offspring function programming by an obesogenic womb are lacking. In this review, we discuss the mechanisms by which an obesogenic intrauterine environment could program the offspring's cardiovascular metabolism in a sex-divergent way, with a special focus on cardiac mitochondrial function, and debate possible strategies to implement during MO pregnancy that could ameliorate, revert, or even prevent deleterious effects of MO on the offspring's cardiovascular system. The impact of maternal physical exercise during an obesogenic pregnancy, nutritional interventions, and supplementation on offspring's cardiac metabolism are discussed, highlighting changes that may be favorable to MO offspring's cardiovascular health, which might result in the attenuation or even prevention of the development of CVD in MO offspring. The objectives of this manuscript are to comprehensively examine the various aspects of MO during pregnancy and explore the underlying mechanisms that contribute to an increased CVD risk in the offspring. We review the current literature on MO and its impact on the offspring's cardiometabolic health. Furthermore, we discuss the potential long-term consequences for the offspring. Understanding the multifaceted effects of MO on the offspring's health is crucial for healthcare providers, researchers, and policymakers to develop effective strategies for prevention and intervention to improve care.

The birth of cardiac disease: Mechanisms linking gestational diabetes mellitus and early onset of cardiovascular disease in offspring.

Cardiovascular disease (CVD) is the biggest killer worldwide, composing a major economic burden for health care systems. Obesity and diabetes are dual epidemics on the rise and major risk factors predisposing for CVD. Increased obesity- and diabetes-related incidence is now observed among children, adolescents, and young adults. Gestational diabetes mellitus (GDM) is the most common metabolic pregnancy disorder, and its prevalence is rapidly increasing. During pregnancies complicated by GDM, the offspring are exposed to a compromised intrauterine environment characterized by hyperglycemic periods. Unfavorable in utero conditions at critical periods of fetal cardiac development can produce developmental adaptations that remodel the cardiovascular system in a way that can contribute to adult-onset of heart disease due to the programming during fetal life. Epidemiological studies have reported increased cardiovascular complications among GDM-descendants, highlighting the urgent need to investigate and understand the mechanisms modulated during fetal development of in utero GDM-exposed offspring that predispose an individual to increased CVD during life. In this manuscript, we overview previous studies in this area and gather evidence linking GDM and CVD development in the offspring, providing new insights on novel mechanisms contributing to offspring CVD programming by GDM, from the role of maternal-fetal interactions to their impact on fetal cardiovascular development, how the perpetuation of cardiac programming is maintained in postnatal life, and advance the intergenerational implications contributing to increased CVD premature origin. Understanding the perpetuation of CVD can be the first step to manage and reverse this leading cause of morbidity and mortality. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Cardiovascular Diseases > Molecular and Cellular Physiology Metabolic Diseases > Genetics/Genomics/Epigenetics.

Metabolic Disease Programming: From Mitochondria to Epigenetics, Glucocorticoid Signalling and Beyond.

Embryonic and foetal development are critical periods of development in which several environmental cues determine health and disease in adulthood. Maternal conditions and an unfavourable intrauterine environment impact foetal development and may programme the offspring for increased predisposition to metabolic diseases and other chronic pathologic conditions throughout adult life. Previously, non-communicable chronic diseases were only associated with genetics and lifestyle. Now the origins of non-communicable chronic diseases are associated with early-life adaptations that produce long-term dysfunction. Early-life environment sets the long-term health and disease risk and can span through multiple generations. Recent research in developmental programming aims at identifying the molecular mechanisms responsible for developmental programming outcomes that impact cellular physiology and trigger adulthood disease. The identification of new therapeutic targets can improve offspring's health management and prevent or overcome adverse consequences of foetal programming. This review summarizes recent biomedical discoveries in the Developmental Origins of Health and Disease (DOHaD) hypothesis and highlight possible developmental programming mechanisms, including prenatal structural defects, metabolic (mitochondrial dysfunction, oxidative stress, protein modification), epigenetic and glucocorticoid signalling-related mechanisms suggesting molecular clues for the causes and consequences of programming of increased susceptibility of offspring to metabolic disease after birth. Identifying mechanisms involved in DOHaD can contribute to early interventions in pregnancy or early childhood, to re-set the metabolic homeostasis and break the chain of subsequent events that could lead to the development of disease.