Hypertension In Offspring Research Articles

Maternal exercise represses FGF21 via SIRT1 to improve the phenotypic transformation of vascular smooth muscle in hypertensive offspring.

Maternal exercise during pregnancy is widely recognized as an effective means of promoting cardiovascular health in offspring. Few studies have explored how maternal exercise impacts vascular function and phenotypic switching in hypertensive offspring, despite the known involvement of vascular structural and functional remodeling in hypertension pathogenesis. Research indicates a significant relationship between elevated blood pressure and fibroblast growth factor 21 (FGF21) levels. It remains unclear whether maternal exercise during pregnancy can improve vascular function in hypertensive offspring by regulating FGF21 and its underlying mechanisms. In this study, pregnant spontaneously hypertensive rats and Wistar-Kyoto rats were randomly assigned to either a sedentary or exercise group. The exercise group underwent weightless swimming exercise from gestation day 1 (GD1) to GD20. The aim was to investigate the epigenetic modifications mediated by histone deacetylase sirtuin 1 (SIRT1) during the fetal period and the phenotypic changes in the mesenteric arteries (MAs) of hypertensive offspring. We found that maternal exercise significantly improved vascular remodeling in hypertensive offspring. Specifically, maternal exercise upregulated SIRT1 expression, which led to decreased H3K9ac (histone H3 lysine 9 acetylation) in the promoter region of the FGF21 gene. This epigenetic modification resulted in the transcriptional downregulation of FGF21 in the MAs of hypertensive fetuses. These results suggest that maternal exercise may lower blood pressure in hypertensive offspring by regulating deacetylation of the FGF21 gene promoter region through SIRT1, thereby reversing phenotypic switching and vascular structural remodeling.

Maternal EGCG intervention mitigates chronic hypertension during pregnancy in spontaneously hypertensive rats without adverse effects on pregnancy outcomes

Background: Chronic hypertension during pregnancy is a significant concern, associated with increased risks of maternal-fetal morbidity and mortality. Epigallocatechin gallate (EGCG), a compound known for its cardioprotective properties, has gained attention as a potential health supplement due to its favorable safety profile. Objective: This study aims to investigate the effects of maternal EGCG supplementation on elevated blood pressure and pregnancy outcomes in a rodent model of chronic hypertension, specifically using spontaneously hypertensive rats (SHR). Furthermore, the study explores the influence of maternal EGCG supplementation on the blood pressure of SHR offspring during early postnatal development. Methods: SHR dams received oral EGCG at 30 mg/kg body weight. Systolic blood pressure (SBP) monitored weekly throughout gestation period and until postpartum day 21. Pregnancy outcomes - litter size, pup viability, and birth weights - were recorded. SBP in weaned SHR offspring was monitored from 5 to 13 weeks of age to assess long-term effects of maternal EGCG treatment. Daily cage-side observations evaluated general health, behavior, and signs of toxicity. Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine were analyzed to evaluate liver and kidney function. Results: EGCG treatment in SHR dams progressively reduced maternal SBP throughout gestation and the postpartum period. However, EGCG administration did not affect pregnancy outcomes (gestation duration, litter size, and birth weights). Markers of liver and kidney function (ALT, AST, urea, and creatinine) showed no signs of organ injury in EGCG-treated groups. Contrary to expectations, SBP in SHR offspring exposed to perinatal EGCG did not decrease compared to control groups, indicating maternal EGCG did not alter the offspring's hypertension predisposition. Conclusion: Maternal EGCG supplementation effectively lowered blood pressure in hypertensive dams without compromising pregnancy outcomes or causing liver and kidney damage. These findings suggest that EGCG may be a safe cardioprotective supplement during pregnancy. However, perinatal EGCG exposure did not alter the inherent genetic predisposition to hypertension in SHR offspring. Keywords: Theaceae; Camellia sinensis; green tea; catechins, EGCG; hypertension, pregnancy outcomes, perinatal, spontaneously hypertensive rats, chronic hypertension during pregnancy

Effect of Purified Resveratrol Butyrate Ester Monomers against Hypertension after Maternal High-Fructose Intake in Adult Offspring.

Offspring hypertension arising from adverse maternal conditions can be mitigated through dietary nutritional supplementation, including resveratrol. Previously, we identified derivatives of resveratrol butyrate ester (RBE), specifically 3,4'-di-O-butanoylresveratrol (ED2) and 3-O-butanoylresveratrol (ED4), demonstrating their superior antioxidant capabilities compared to RBE itself. This study sought to assess the protective impact of maternal supplementation with ED2 or ED4 on offspring hypertension in a rat model subjected to a high-fructose (HF) diet during pregnancy and lactation. Female Sprague-Dawley rats were distributed into distinct dietary groups throughout pregnancy and lactation: (1) standard chow; (2) HF diet (60%); (3) HF diet supplemented with ED2 (25 mg/L); and (4) HF diet supplemented with ED4 (25 mg/L). Male offspring were euthanized at the age of 12 weeks. The maternal HF diet induced hypertension in the offspring, which was mitigated by perinatal supplementation with either ED2 or ED4. These protective effects were attributed to the antioxidant properties of ED2 and ED4, resulting in an increased availability of nitric oxide (NO). Additionally, supplementation with ED2 was connected to an increased abundance of Bifidobacterium and Clostridium genera, which was accompanied by a decrease in Angelakisella and Christensenella. On the other hand, ED4 supplementation shielded rat offspring from hypertension by elevating concentrations of short-chain fatty acids (SCFAs) and their receptors while reducing trimethylamine-N-oxide (TMAO) levels. These findings highlight the potential of purified RBE monomers, ED2 and ED4, as preventive measures against hypertension resulting from a maternal high-fructose diet. Further research is warranted to explore their clinical applications based on these promising results.

Lactoferrin Supplementation during Pregnancy and Lactation Protects Adult Male Rat Offspring from Hypertension Induced by Maternal Adenine Diet.

Lactoferrin, a glycoprotein derived from breastmilk, is recognized for its health benefits in infants and children; however, its protective effects when administered during gestation and lactation against offspring hypertension remain unclear. This study aimed to investigate whether maternal lactoferrin supplementation could prevent hypertension in offspring born to mothers with chronic kidney disease (CKD), with a focus on nitric oxide (NO), renin-angiotensin system (RAS) regulation, and alterations in gut microbiota and short-chain fatty acids (SCFAs). Prior to pregnancy, female rats were subjected to a 0.5% adenine diet for 3 weeks to induce CKD. During pregnancy and lactation, pregnant rats received one of four diets: normal chow, 0.5% adenine diet, 10% lactoferrin diet, or adenine diet supplemented with lactoferrin. Male offspring were euthanized at 12 weeks of age (n = 8 per group). Supplementation with lactoferrin during gestation and lactation prevented hypertension in adult offspring induced by a maternal adenine diet. The maternal adenine diet caused a decrease in the index of NO availability, which was restored by 67% with maternal LF supplementation. Additionally, LF was related to the regulation of the RAS, as evidenced by a reduced renal expression of renin and the angiotensin II type 1 receptor. Combined maternal adenine and LF diets altered beta diversity, shifted the offspring's gut microbiota, decreased propionate levels, and reduced the renal expression of SCFA receptors. The beneficial effects of lactoferrin are likely mediated through enhanced NO availability, rebalancing the RAS, and alterations in gut microbiota composition and SCFAs. Our findings suggest that maternal lactoferrin supplementation improves hypertension in offspring in a model of adenine-induced CKD, bringing us closer to potentially translating lactoferrin supplementation clinically for children born to mothers with CKD.

Chondroitin Sulfate Ameliorates Hypertension in Male Offspring Rat Born to Mothers Fed an Adenine Diet.

Pregnant women with chronic kidney disease (CKD) face increased risks of adverse outcomes in their adult offspring. Offspring rats born to dams fed an adenine diet develop hypertension, coinciding with dysregulated hydrogen sulfide (H2S) and nitric oxide (NO) pathways, as well as alterations in gut microbiota. Chondroitin sulfate (CS) is a multifunctional food known for its diverse bioactivities. As a sulfate prebiotic, CS has shown therapeutic potential in various diseases. Here, we investigated the protective effects of maternal CS supplementation against hypertension in offspring induced by an adenine diet. Mother rats were administered regular chow, 0.5% adenine, 3% CS, or a combination throughout gestation and lactation. Maternal CS supplementation effectively protected offspring from hypertension induced by the adenine diet. These beneficial effects of CS were connected with increased renal mRNA and protein levels of 3-mercaptopyruvate sulfurtransferase, an enzyme involved in H2S production. Furthermore, maternal CS treatment significantly enhanced alpha diversity and altered beta diversity of gut microbiota in adult offspring. Specifically, perinatal CS treatment promoted the abundance of beneficial microbes such as Roseburia hominis and Ruminococcus gauvreauii. In conclusion, perinatal CS treatment mitigates offspring hypertension associated with maternal adenine diet, suggesting that early administration of sulfate prebiotics may hold preventive potential. These findings warrant further translational research to explore their clinical implications.

Maternal hypothyroidism and subsequent metabolic outcomes in children: a systematic review and meta-analysis

IntroductionAs the fetus relies on maternal thyroid hormones in early pregnancy, maternal hypothyroidism plays an important role in fetal development. However, the association between maternal hypothyroidism and metabolic disease in offspring is unclear.ObjectiveTo examine the association between maternal hypothyroidism in pregnancy and metabolic outcomes (obesity, hypertension, type 2 diabetes mellitus, and dyslipidemia) in children < 18 years.MethodsWe systematically searched 5 databases from inception to May 2023. Eligible studies included cohort, case-control, and randomized controlled trials involving children born to mothers with or without hypothyroidism in pregnancy. Data were pooled across studies using random-effects models for outcomes reported in at least three studies. Quality assessment was performed using the ROBINS-E tool for observational studies and the Cochrane Risk of Bias tool for trials.ResultsThe search identified 3221 articles, of which 7 studies were included (1 trial, 6 observational). All studies were conducted outside of North America and ranged in size from 250 to > 1 million children. The follow-up time ranged from 6 to 20 years. Included studies support an increased risk of hypertension and glucose dysregulation in offspring exposed to maternal hypothyroidism (hypertension: OR 1.08, 95% CI 0.75, 1.57 and HR 1.81, 95% CI 1.21, 2.69; diabetes: RR 2.7, 95% CI 0.7, 10). In the pooled analysis, maternal hypothyroidism was not associated with obesity in offspring (OR 1.04, 95% CI 0.64, 1.70).ConclusionThis study found inconsistent evidence on the association between maternal hypothyroidism in pregnancy and metabolic outcomes in offspring, though associations with hypertension and glucose dysregulation are possible.

AT1-AA Induced Placental Ischemia Contributes to Hypertension in Female Offspring

Objective: Preeclampsia (PE), new-onset hypertension during the third trimester of pregnancy alongside other organ dysfunction, is associated with chronic inflammation and fetal growth restriction. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA) are produced in PE women and induce a PE-like phenotype when infused into pregnant rats. AT1-AA is still present in maternal circulation up to eight years postpartum. We have shown that AT1-AA exposure during pregnancy contributes to impairment of cerebral blood flow in the postpartum period. Moreover, PE offspring are at higher risk for cardiovascular disease and hypertension but AT1-AA’s role in this elevated risk is unknown. The objective of this study was to determine if AT1-AA contributes to the risk for hypertension in PE offspring. Therefore, we hypothesized that AT1-AA infusion during pregnancy would cause offspring to have low birth weight and hypertension in adulthood. Methods: We infused AT1-AA (1:40) starting on gestational day (GD) 14 and allowed the dams to give birth on GD21. Birth weight was measured within 12 hours. Offspring were aged to 4 months. At that time, one male and female per litter were randomly selected to undergo carotid catheterization. The following day mean arterial pressure (MAP) was measured and blood and tissues were collected. Immune cells were measured by flow cytometry. Sex hormones were measured by mass spectroscopy. AT1-AA was measured by cardiomyocyte bioassay. Renal endothelin was measured by ELISA and RT-PCR. A two-way ANOVA was used for statistical analysis. Results: AT1-AA male and female offspring (6.1±0.1g, n=19, p&lt;0.05; 5.8±0.1g, n=19, p&lt;0.05) were larger at birth than NP male and female offspring (5.8±0.1g, n=11; 5.5±0.1g, n=11). Female AT1-AA offspring had elevated MAP (124±2 mmHg, n=14, p&lt;0.05) compared to NP female offspring (110±5 mmHg, n=8) while male AT1-AA offspring had similar MAP to male NP offspring. Circulating cytolytic NK cells trended higher in female AT1-AA offspring (2.73±0.37 % gated, n=9, p=0.0949) compared to female NP offspring (1.66±0.31 % gated, n=6). Female AT1-AA offspring also had elevated progesterone (41.3±6.0 pg/μL, n=8, p=0.0556) compared to female NP offspring (26.9±4.9 pg/μL, n=7). Renal PPET expression was increased in female AT1-AA offspring (2.6±0.69 fold increase, n=4, p&lt;0.05) compared to female NP offspring. Renal endothelin-1 was increased in female AT1-AA offspring (1.02±0.23 pg/mg, n=7, p=0.062) compared to female NP offspring (0.59±0.06 pg/mg, n=6). Male and female AT1-AA offspring had increased circulating AT1-AA (9.5±2.2 ΔBPM, n=6, p&lt;0.0001; 7.9±0.9 ΔBPM, n=8, p&lt;0.001) compared to male and female NP offspring (-0.4±.4 ΔBPM, n=7; -0.8±0.4 ΔBPM, n=4). Conclusion: These data demonstrate that AT1-AA infusion during pregnancy can predispose female offspring to have elevated blood pressure in adulthood. This study was supported by NIH grants RO1HD067541 (BL), F31HD110230 (NC), P20GM121334 (BL, LMA), HL151407 (DCC) and American heart association (AHA) early career award 19CDA34670055 (LMA). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exploring the impact of prenatal perfluoroalkyl and polyfluoroalkyl substances exposure on blood pressure in early childhood: A longitudinal analysis

Previous research investigating the correlation between prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and subsequent blood pressure (BP) in offspring has yielded limited and contradictory findings. This study was conducted to investigate the potential relationship between maternal PFAS levels during pregnancy and subsequent BP in early childhood. A total of 129 expectant mothers from the Shanghai Birth Cohort were included in the study. Using high-performance liquid chromatography/tandem mass spectrometry, we measured ten PFAS compounds in maternal plasma throughout the pregnancy. When the children reached the age of 4, we examined their systolic BP (SBP) and diastolic BP (DBP), along with mean arterial pressure (MAP) and pulse pressure (PP). Data interpretation employed multiple linear and logistic regression models, complemented by Bayesian kernel machine regression (BKMR).We found that the majority of PFAS concentrations remained stable during pregnancy. The linear and BKMR models indicated a positive relationship between the PFAS mixture in maternal plasma and offspring's DBP and MAP, with perfluorohexanesulphonic acid (PFHxS) having the most significant influence (PFHxS and DBP [first trimester:β=3.03, 95%CI: (1.01,5.05); second trimester: β=2.35, 95%CI: (0.94,3.75); third trimester: β=2.57, 95%CI:(0.80,4.34)]; MAP [first trimester:β=2.55, 95%CI: (0.64,4.45); second trimester: β=2.28, 95%CI: (0.95,3.61); third trimester: β=2.35, 95%CI:(0.68,4.01)]). Logistic regression highlighted an increased risk of prehypertension and hypertension in offspring with higher maternal PFHxS concentrations during all three trimesters [first trimester: OR=2.53, 95%CI:(1.11,5.79), second trimester: OR=2.05, 95%CI:(1.11,3.78), third trimester: OR=3.08, 95%CI:(1.40,6.79)]. A positive correlation was identified between the half-lives of PFAS and the odds ratio (OR) of prehypertension and hypertension in childhood (β=0.139, P=0.010). In conclusion, this research found maternal plasma PFAS concentrations to be positively associated with BP in offspring, with PFHxS showing the most significant influence. This correlation remained consistent throughout pregnancy, and this effect was proportional to the half-lives of PFAS.

Effect of parental hypertension on heart rate variability

Background: Nowadays, pre-hypertension is common in young adults, especially children of hypertensive parents who are more prone to it. One of the earliest signs of hypertension is sympathovagal imbalance, which can be detected by heart rate variability (HRV) even at a subclinical stage. This study helps us to analyze HRV among the offspring of hypertensive and normotensive parents. Aims and Objectives: The objective is to compare and analyze HRV among offspring of hypertensive parents and normotensive parents. Materials and Methods: 60 healthy young adolescent males (age 18–20 years) were involved in the study. Out of which 30 are offspring of hypertensive parents, 30 are offspring of non-hypertensive parents. HRVs were recorded. Results were tabulated and analyzed by the student “t” test. Results: Low-to-high frequency (LF/HF) ratio, normalized high frequency (HFnu), and normalized low frequency (LFnu) values were compared between offspring of hypertensive parents and normotensive parents. It was found to be significant by the student “t” test [“P” &lt; 0.05]. Conclusion: In my study, an increased LF/HF ratio and LFnu and decreased HFnu were noted in the offspring of hypertensive parents. It denotes a sympathovagal imbalance. The autonomic nervous system can be accurately assessed by HRV, which is helpful for the early diagnosis of hypertension. Early diagnosis of hypertension in high-risk people using HRV is helpful to avoid further cardiovascular and cerebrovascular complications.

Cardiovascular effect of preeclampsia upon offspring development: Are (Pro) renin-renin receptor ((P)RR) and gender related?

Preeclampsia (PE) is a complication of pregnancy that might increase progeny risk of cardiovascular and metabolic problems, mainly in males. Renin angiotensin aldosterone system is known to be involved. (Pro) renin/renin receptor ((P)RR) has been shown to participate in cardiovascular pathology. The aim of this work was to evaluate (P)RR expression and function upon cardiovascular and renal tissues from PE dams' offspring. We used offspring from normal pregnant and preeclamptic rats, evaluating body, heart, aorta and kidney weight, length, and blood pressure along 3 months after birth. Subsets of animals received handle region peptide (HRP) (0.2 mg/Kg, sc). Another group received vehicle. Animals were sacrificed at first, second, and third months of age, tissues were extracted and processed for immunoblot to detect (P)RR, PLZF, β-catenin, DVL-1, and PKCα. (P)RR and PLZF were also measured by RT-PCR. We found that offspring developed hypertension. Male descendants remained hypertensive throughout the whole experiment. Female animals tended to recover at second month and returned to normal blood pressure at third month. HRP treatment diminished hypertension in both male and female animals. Morphological evaluations showed changes in heart, aorta, and kidney weight, and HRP reverted this effect. Finally, we found that (P)RR, PLZF, and canonical WNT transduction pathway molecules were stimulated by PE, and HRP treatment abolished this increase. These findings suggest that PE can induce hypertension in offspring, and (P)RR seems to play an important role through the canonical WNT pathway and that gender seems to influence this response.

Gestational Intermittent Hypoxia Impairs AT2R-Mediated Vascular Protection in Female Offspring on a High-Fat, High-Sucrose Diet.

Gestational intermittent hypoxia (GIH), a hallmark of maternal obstructive sleep apnea, sex-differentially causes hypertension and endothelial dysfunction in adult male offspring but not in females. This study investigated whether the GIH-exposed female offspring, a "protected" group against the hypertensive effects of maternal GIH exposure, exhibit increased susceptibility to hypertension and cardiovascular dysfunction when fed a high-fat high-sucrose (HFHS) diet and whether this effect could be reversed by pharmacological intervention activating the angiotensin II type 2 receptor (AT2R). Female offspring of control and GIH-exposed (10.5% O2, 8 h/d, E10-21) dams were assigned either an HFHS diet or a standard diet from 12 weeks of age. Blood pressure was monitored. At 28 weeks, a systemic CGP42112 (AT2R agonist) or saline infusion was administered through the osmotic pump. At 30 weeks, the heart was weighed and collected for H&E staining, mesenteric arteries for vascular reactivity assessment and protein analysis, and plasma for ELISA. The HFHS diet induced similar increases in body weight gain and blood pressure in control and GIH female offspring. HFHS feeding did not affect heart structure, but impaired endothelial-dependent vascular relaxation with associated decreased AT2R and eNOS expression and reduced plasma bradykinin levels in both control and GIH offspring. CGP42112 administration effectively mitigated HFHS-induced hypertension and endothelial dysfunction only in control offspring, accompanied by restored AT2R, eNOS, and bradykinin levels, but not in the GIH counterparts. These findings suggest that GIH induces endothelial dysfunction and AT2R insensitivity in female offspring exposed to an HFHS diet.

Protective Role of Taurine on Rat Offspring Hypertension in the Setting of Maternal Chronic Kidney Disease.

Taurine is a natural antioxidant with antihypertensive properties. Maternal chronic kidney disease (CKD) has an impact on renal programming and increases the risk of offspring hypertension in later life. The underlying mechanisms cover oxidative stress, a dysregulated hydrogen sulfide (H2S) system, dysbiotic gut microbiota, and inappropriate activation of the renin-angiotensin-aldosterone system (RAAS). We investigated whether perinatal taurine administration enables us to prevent high blood pressure (BP) in offspring complicated by maternal CKD. Before mating, CKD was induced through feeding chow containing 0.5% adenine for 3 weeks. Taurine was administered (3% in drinking water) during gestation and lactation. Four groups of male offspring were used (n = 8/group): controls, CKD, taurine-treated control rats, and taurine-treated rats with CKD. Taurine treatment significantly reduced BP in male offspring born to mothers with CKD. The beneficial effects of perinatal taurine treatment were attributed to an augmented H2S pathway, rebalance of aberrant RAAS activation, and gut microbiota alterations. In summary, our results not only deepen our knowledge of the mechanisms underlying maternal CKD-induced offspring hypertension but also afford us the impetus to consider taurine-based intervention as a promising preventive approach for future clinical translation.

Metabolomics to Understand Alterations Induced by Physical Activity during Pregnancy.

Physical activity (PA) and exercise have been associated with a reduced risk of cancer, obesity, and diabetes. In the context of pregnancy, maintaining an active lifestyle has been shown to decrease gestational weight gain (GWG) and lower the risk of gestational diabetes mellitus (GDM), hypertension, and macrosomia in offspring. The main pathways activated by PA include BCAAs, lipids, and bile acid metabolism, thereby improving insulin resistance in pregnant individuals. Despite these known benefits, the underlying metabolites and biological mechanisms affected by PA remain poorly understood, highlighting the need for further investigation. Metabolomics, a comprehensive study of metabolite classes, offers valuable insights into the widespread metabolic changes induced by PA. This narrative review focuses on PA metabolomics research using different analytical platforms to analyze pregnant individuals. Existing studies support the hypothesis that exercise behaviour can influence the metabolism of different populations, including pregnant individuals and their offspring. While PA has shown considerable promise in maintaining metabolic health in non-pregnant populations, our comprehension of metabolic changes in the context of a healthy pregnancy remains limited. As a result, further investigation is necessary to clarify the metabolic impact of PA within this unique group, often excluded from physiological research.

Prenatal Nicotine Exposure Raises Male Blood Pressure via FTO-Mediated NOX2/ROS Signaling.

Cigarette smoking/nicotine exposure in pregnancy shows an increased risk of hypertension in offspring, but the mechanisms are unclear. This study tested the hypothesis that m6A RNA hypomethylation epigenetically regulates vascular NOX (NADPH oxidase) and reactive oxygen species production, contributing to the fetal programming of a hypertensive phenotype in nicotine-exposed offspring. Pregnant rats were exposed to episodic chronic intermittent nicotine aerosol (CINA) or saline aerosol control from gestational day 4 to day 21, and experiments were performed in 6-month-old adult offspring. Antenatal CINA exposure augmented Ang II (angiotensin II)-stimulated blood pressure response in male, but not female offspring. Moreover, CINA increased vascular NOX2 expression and superoxide production exclusively in male offspring. Inhibition of NOX2 with gp91ds-tat, both ex vivo and in vivo, mitigated the CINA-induced elevation in superoxide production and blood pressure response. Notably, CINA enhanced the expression of vascular m6A demethylase FTO (fat mass and obesity-associated protein), while reducing the total vascular m6A abundance and specific m6A methylation of the NOX2 gene. Additionally, ex vivo inhibition of FTO with FB23-2 attenuated CINA-induced increases in vascular NOX2 expression. In vitro experiments using human umbilical vein endothelial cells demonstrated that nicotine dose-dependently upregulated FTO and NOX2 protein abundance, which were reversed by treatment with the FTO inhibitor FB23-2 or FTO knockdown using siRNAs. This study uncovers a new mechanism: m6A demethylase FTO-mediated epigenetic upregulation of vascular NOX2 signaling in CINA-induced hypertensive phenotype. This insight could lead to a therapeutic target for preventing and treating developmental hypertension programming.

The Epigenetic Legacy of Maternal Protein Restriction: Renal Ptger1 DNA Methylation Changes in Hypertensive Rat Offspring.

Nutrient imbalances during gestation are a risk factor for hypertension in offspring. Although the effects of prenatal nutritional deficiency on the development of hypertension and cardiovascular diseases in adulthood have been extensively documented, its underlying mechanisms remain poorly understood. In this study, we aimed to elucidate the precise role and functional significance of epigenetic modifications in the pathogenesis of hypertension. To this end, we integrated methylome and transcriptome data to identify potential salt-sensitive hypertension genes using the kidneys of stroke-prone spontaneously hypertensive rat (SHRSP) pups exposed to a low-protein diet throughout their fetal life. Maternal protein restriction during gestation led to a positive correlation between DNA hypermethylation of the renal prostaglandin E receptor 1 (Ptger1) CpG island and high mRNA expression of Ptger1 in offspring, which is consistently conserved. Furthermore, post-weaning low-protein or high-protein diets modified the Ptger1 DNA hypermethylation caused by fetal malnutrition. Here, we show that this epigenetic variation in Ptger1 is linked to disease susceptibility established during fetal stages and could be reprogrammed by manipulating the postnatal diet. Thus, our findings clarify the developmental origins connecting the maternal nutritional environment and potential epigenetic biomarkers for offspring hypertension. These findings shed light on hypertension prevention and prospective therapeutic strategies.

Abstract P210: Sex Specific Changes In Cerebral Proinflammatory Cytokines In Intrauterine Growth Restricted Offspring

Background: Intrauterine growth restriction (IUGR) often times results from placental ischemia, which restricts the distribution of nutrients and oxygen to meet the metabolic demand of the growing fetus. IUGR offspring (OS) have an increased risk for developing cerebrovascular diseases (CVD) later in life. Factors for development of CVDs are HTN and inflammation. Our lab has shown 17 week IUGR male rats from preeclamptic pregnancies have HTN and elevated inflammation via systemic IL-17, while our females show no change. The role of inflammation to cause HTN in IUGR offspring in a sex specific manner is unknown and the major focus of this study which examines the changes in cerebral inflammation IUGR offspring at 12 weeks. We hypothesize that cerebral inflammation in IUGR males will be elevated, while no change in female IUGR offspring will be observed. Methods: IUGR offspring originate from preeclamptic Sprague Dawley dams. OS weaned for 3 weeks and were separated by sex and IUGR status. At 12 weeks, the rats underwent carotid catheterization to measure BP. Brains were collected to measure pro-inflammatory cytokines, such as TNF-α and IL-17 via ELISAs. Results: At 12 weeks, all OS were normotensive. Brain TNF-α increased in female IUGR (17,366± 1,500 vs 8,116± 1,341 pg/mL, p&lt;0.05) and was elevated in male IUGR (20,845±7571 vs 8,516±1712 pg/mL, ns). Brain IL-17 increased in male IUGR (13,580± 945 vs 9,620± 945 pg/mL, p&lt;0.05) and was elevated in female IUGR (13,143± 1613 vs 10,930± 696 pg/mL, ns). Systemic IL-17 was increased in IUGR male OS (112±16.8vs100±3.9 IU/Protein/CON %, ns). Conclusion: At 12 weeks, brain TNF-α and IL-17 were elevated in IUGR males and females. The differences in expression of each cytokine between the sexes suggest that IL-17 contributes to the increase in BP, especially in males. Understanding the timing of these developments could help to elucidate the role of inflammation in the development of CVD with or without HTN. This study is clinically relevant as it provides a sex specific inflammatory target for therapeutics, to help prevent hypertension and CVD in IUGR offspring. In the future, we will evaluate the role of inflammation in IUGR offspring in a sex specific manner.

Risk of Adult Hypertension in Offspring From Pregnancies Complicated by Hypertension: Population-Based Estimates.

Hypertensive disorders of pregnancy (HDP) have been associated with an increased risk of chronic hypertension for both mothers and offspring. We sought to quantify the incidence of chronic hypertension in offspring from HDP-affected pregnancies in a large, population-based cohort study. Furthermore, we evaluate the association of HDP exposure in utero and maternal chronic hypertension in offspring. We performed a population-based cohort study of 8755 individuals born during 1976 to 1982 to 7544 women who all resided in the same community at the time of delivery. HDP were identified using a previously validated algorithm. Diagnosis of chronic hypertension in mothers and their offspring was determined using diagnostic codes. Cox proportional hazards regression was used to assess the association between HDP and chronic hypertension. HDP exposure (hazard ratio, 1.50 [95% CI, 1.18-1.90]) and maternal chronic hypertension (hazard ratio, 1.73 [95% CI, 1.48-2.02]) were both associated with a significant increased risk for chronic hypertension in offspring. Both risk factors remained significantly associated with increased risk of hypertension in offspring when included together in a multivariate model. Having both exposures was associated with a 2.4-fold increase in the risk of hypertension in offspring, suggesting a synergistic additive interaction. HDP exposure in gestation and maternal hypertension are both independently associated with an increased risk of chronic hypertension in offspring. Our results suggest that HDP exposure in utero, in addition to maternal chronic hypertension, may lead to a greater risk for the development of hypertension in offspring.

Maternal exercise represses Nox4 via SIRT1 to prevent vascular oxidative stress and endothelial dysfunction in SHR offspring.

Maternal exercise during pregnancy has emerged as a potentially promising approach to protect offspring from cardiovascular disease, including hypertension. Although endothelial dysfunction is involved in the pathophysiology of hypertension, limited studies have characterized how maternal exercise influences endothelial function of hypertensive offspring. In this study, pregnant spontaneously hypertensive rats and Wistar-Kyoto rats were assigned either to a sedentary lifestyle or to swimming training daily, and fetal histone deacetylase-mediated epigenetic modification and offspring vascular function of mesenteric arteries were analyzed. Maternal exercise ameliorated the impairment of acetylcholine-induced vasodilation without affecting sodium nitroprusside-induced vasodilation in mesenteric arteries from the hypertensive offspring. In accordance, maternal exercise reduced NADPH oxidase-4 (Nox4) protein to prevent the loss of nitric oxide generation and increased reactive oxygen species production in mesenteric arteries of hypertensive offspring. We further found that maternal exercise during pregnancy upregulated vascular SIRT1 (sirtuin 1) expression, leading to a low level of H3K9ac (histone H3 lysine 9 acetylation), resulting in the transcriptional downregulation of Nox4 in mesenteric arteries of hypertensive fetuses. These findings show that maternal exercise alleviates oxidative stress and the impairment of endothelium-dependent vasodilatation via SIRT1-regulated deacetylation of Nox4, which might contribute to improved vascular function in hypertensive offspring.

Acute effect of various dosages of sugar ingestion on vascular function in offspring of hypertensive and normotensive parents.

We aimed to study vascular function in healthy men with a parental history of hypertension compared to those without. Acute effect of various dosages of sugar ingestion on vascular function was also investigated in both groups. Thirty-two healthy men were recruited and divided into two groups, offspring of hypertensive parents (OHT) and offspring of normotensive parents (ONT). Participants were orally given 15, 30, and 60 g of sucrose solution compared to water. Peak forearm blood flow (FBF), forearm vascular resistance (FVR), pulse wave velocity (PWV), and oxidative stress markers were measured at baseline and after sucrose intake at 30, 60, 90, and 120 min. At baseline, peak FBF was significantly lower (22.40 ± 1.18 vs. 25.24 ± 0.63 ml × dl -1 × min -1 , P < 0.001), FVR was significantly higher (3.73 ± 0.42 vs. 3.30 ± 0.26 mmHg × ml -1 × dl × min, P = 0.002), and PWV was significantly faster (6.31 ± 0.59 vs. 5.78 ± 0.61 m/s, P = 0.017) in OHT than ONT. After each sucrose intake, peak FBF significantly declined and was lowest at 30 min in both groups. The reduction in peak FBF was seen in all doses of sucrose and the higher dose of sucrose intervened, the longer reduction in peak FBF observed. Vascular function was attenuated in healthy men with a family history of hypertension and became worse after sucrose ingestion even at the low dose. Our findings suggest that the ones, especially those with a parental history of hypertension, should reduce sugar consumption as low as possible.

Protection by Means of Perinatal Oral Sodium Thiosulfate Administration against Offspring Hypertension in a Rat Model of Maternal Chronic Kidney Disease.

Hydrogen sulfide (H2S) and related reactive sulfur species are implicated in chronic kidney disease (CKD) and hypertension. Offspring born to CKD-afflicted mothers could develop hypertension coinciding with disrupted H2S and nitric oxide (NO) signaling pathways as well as gut microbiota. Thiosulfate, a precursor of H2S and an antioxidant, has shown anti-hypertensive effects. This study aimed to investigate the protective effects of sodium thiosulfate (STS) in a rat model of maternal CKD-induced hypertension. Before mating, CKD was induced through feeding 0.5% adenine chow for 3 weeks. Mother rats were given a vehicle or STS at a dosage of 2 g/kg/day in drinking water throughout gestation and lactation. Perinatal STS treatment protected 12-week-old offspring from maternal CKD-primed hypertension. The beneficial effects of STS could partially be explained by the enhancement of both H2S and NO signaling pathways and alterations in gut microbiota. Not only increasing beneficial microbes but maternal STS treatment also mediates several hypertension-associated intestinal bacteria. In conclusion, perinatal treatment with STS improves maternal CKD-primed offspring hypertension, suggesting that early-life RSS-targeting interventions have potential preventive and therapeutic benefits, awaiting future translational research.