Hypertension In Offspring Research Articles

Sex differences in cerebrovascular dysfunction and hypertension in offspring of hypertensive pregnant rats

BACKGROUNDOffspring from preeclamptic women have a greater risk of hypertension and cerebrovascular dysfunction later in life. One of the major contributors of cerebrovascular dysfunction is impaired cerebral blood flow (CBF) autoregulation. In the USA, 1 in 25 pregnancies are preeclamptic. Preeclampsia, as defined as new‐onset hypertension during pregnancy, is an inflammatory condition characterized by elevated interleukin 17 (IL‐17), mitochondrial reactive oxygen species (mtROS), mitochondrial dysfunction (mt‐Dys), and intrauterine growth restriction (IUGR). Preliminary work from our laboratory demonstrates that offspring from preeclamptic rats have sex differences. Males have hypertension and a greater impairment of CBF autoregulation, while females have no change in blood pressure with impaired CBF autoregulation. The exact mechanisms for the sex differences in cerebrovascular dysfunction and hypertension is unknown and is the focus of this study. We hypothesize that changes in cerebral mt‐Dys, cerebral mtROS, and circulating IL‐17 contributes to the sex differences in hypertension and cerebrovascular dysfunction in male and female offspring from preeclamptic rats.METHODSIn this study, we compared male and female offspring from normal pregnant and preeclamptic Sprague Dawley rats. All offspring were divided into controls (CON) and IUGR by sex. Hypertensive male and non‐hypertensive female offspring’s with impaired CBF autoregulation were examined at 17 weeks of age for changes in cerebral mitochondrial electron transport chain (ETC) protein complexes, cerebral manganese superoxide dismutase (MnSOD), and circulating IL‐17.RESULTSFemale CON (151±5% IU/Protein/male CON) and IUGR (149±8 %IU/Protein/male CON) offspring have increased MnSOD compared to CON (100±7 %IU/Protein/male CON) and IUGR (122±4 %IU/Protein/male CON) males (p<0.05). No changes in female ETC protein complexes between IUGR and CON. Male IUGR have a decrease in complex II (71±5 vs. 100±8 %IU/Protein/male CON, p<0.05) and V (57±2 vs. 100±10 %IU/Protein/male CON, p<0.05) ETC proteins, and elevated IL‐17 (944±370 vs. 412±115 pg/mL, ns) compared to CON males.CONCLUSIONMale IUGR offspring have mt‐Dys and elevated IL‐17, which may contribute to hypertension and a greater impairment in CBF autoregulation. Female IUGR offspring may be protected due to an increase in mitochondrial antioxidants. In summary, studying the dimorphic sex differences in the mechanisms of hypertension and cerebrovascular dysfunction in offspring of preeclamptic women, may improve the offspring’s risk of hypertension, cardiovascular disease, stroke, and cognitive dysfunction later in life.

The mediating pathways between parental separation in childhood and offspring hypertension at midlife

Social life course determinants of adult hypertension are relatively unknown. This paper examines how parental separation before age 10 relates to hypertension at age 46. Adjusting for parental confounders and considering the role of adult mediators, we aim to quantify unexplored mediating pathways in childhood using prospectively collected data. Data from the 1970 British Birth Cohort Study are utilised. Hypertension is measured by health care professionals at age 46. Potential mediating pathways in childhood include body mass index (BMI), systolic and diastolic blood pressure, illness, disability, family socioeconomic status (SES) and cognitive and developmental indicators at age 10. Additionally, we explore to what extent childhood mediators operate through adult mediators, including health behaviours, family SES, BMI and mental wellbeing. We also test for effect modification of the relationship between parental separation and hypertension by gender. Nested logistic regression models test the significance of potential mediating variables. Formal mediation analysis utilising Karlson Holm and Breen (KHB) method quantify the direct and indirect effect of parental separation on offspring hypertension at midlife. There was an association between parental separation and hypertension in mid-life in women but not men. For women, family SES and cognitive and behavioural development indicators at age 10 partly mediate the relationship between parental separation and hypertension at age 46. When adult mediators including, health behaviours, family SES, BMI and mental wellbeing are included, the associations between the childhood predictors and adult hypertension are attenuated, suggesting that these childhood mediators in turn may work through adult mediators to affect the risk of hypertension in midlife. We found family SES in childhood, cognitive and behaviour development indicators at age 10, including disruptive behaviour, coordination and locus of control in childhood, to be important mediators of the relationship between parental separation and midlife hypertension suggesting that intervening in childhood may modify adult hypertension risk.

Limosilactobacillus fermentum prevents gut-kidney oxidative damage and the rise in blood pressure in male rat offspring exposed to a maternal high-fat diet.

Oxidative stress along the gut-kidney axis is a risk factor for developing arterial hypertension in offspring from dams fed a high-fat diet. Considering the antioxidant capacity of probiotic strains, this study evaluated the effects of a daily multistrain formulation with Limosilactobacillus fermentum 139, 263, and 296 on blood pressure (BP), renal function, and oxidative stress and along the gut-kidney axis in male offspring from dams fed a high-fat high-cholesterol (HFHC) diet during pregnancy and lactation. Dams were fed a diet control or HFHC diet during pregnancy and lactation. At 100 days of age, part of the male offspring from dams fed a HFHC diet received Limosilactobacillus fermentum formulation for 4 weeks (HFHC + Lf) daily. After the 4-week intervention, BP (tail-cuff plethysmography) and urinary and biochemical variables were measured. In addition, malondialdehyde levels, enzymatic activities of superoxide dismutase, catalase, glutathione-S-transferase, and nonenzymatic antioxidant defense (thiols content) were measured in the colon and renal cortex. Male offspring from dams fed a HFHC had increased blood pressure, impaired renal function, and oxidative stress along the gut-kidney axis. Administration of Limosilactobacillus fermentum reduced systolic, diastolic, and mean blood pressure levels and alleviated renal function impairment and oxidative stress along the gut-kidney axis in male offspring from dams fed a HFHC diet. Administration of Limosilactobacillus fermentum formulation attenuated programmed hypertension in the HFHC group through oxidative stress modulation along the gut-kidney axis.

Maternal high salt-diet increases offspring's blood pressure with dysfunction of NO/PKGI signaling pathway in heart tissue

BackgroundHigh salt-diets have become significant threats to human health, resulting in hypertension and cardiovascular diseases. Hypertensive disorders during pregnancy are complicated, since the maternal cardiovascular system undergoes extensive physiological changes during pregnancy. High-salt diets during pregnancy can disturb the intrauterine environment and negatively affect fetal development. Therefore, we explored how high-salt diets during pregnancy could affect the offspring. MethodsRats were divided into three groups and fed with low, normal, and high salt diets. The offspring were separated into three groups after weaning based on dietary salt concentration. The blood pressure and urine protein content of both dams and offspring were measured. To evaluate cardiac function, we used Masson staining and immunodetection to confirm the fibrosis status. Finally, we extracted protein from cardiac tissue to test the expression levels of the Nitric Oxide (NO)/cGMP-dependent protein kinase I (PKGI) pathway and the angiotensin receptor. ResultsHigh-salt diets increased blood pressure, and offspring previously exposed to high-salt environments were predisposed to hypertension. High-salt diets were also found to induce cardiac fibrosis and exacerbate fibrosis in offspring and alter the epithelial-mesenchymal transition (EMT). Under these conditions, the NO/PKGI pathway was activated in cardiac tissue and the type-1angiotensin II receptor (AT1R) was upregulated, though the type-2 angiotensin II receptor (AT2R) had the opposite effect. ConclusionHigh-salt diets induce high blood pressure and increase predisposition to hypertension in offspring. They are accompanied by cardiac fibrosis, which could be caused by the activation of NO/PKGI and upregulation of AT1R.

Oxidative Stress-Induced Hypertension of Developmental Origins: Preventive Aspects of Antioxidant Therapy.

Hypertension remains the leading cause of disease burden worldwide. Hypertension can originate in the early stages of life. A growing body of evidence suggests that oxidative stress, which is characterized as a reactive oxygen species (ROS)/nitric oxide (NO) disequilibrium, has a pivotal role in the hypertension of developmental origins. Results from animal studies support the idea that early-life oxidative stress causes developmental programming in prime blood pressure (BP)-controlled organs such as the brain, kidneys, heart, and blood vessels, leading to hypertension in adult offspring. Conversely, perinatal use of antioxidants can counteract oxidative stress and therefore lower BP. This review discusses the interaction between oxidative stress and developmental programming in hypertension. It will also discuss evidence from animal models, how oxidative stress connects with other core mechanisms, and the potential of antioxidant therapy as a novel preventive strategy to prevent the hypertension of developmental origins.

Dietary Supplementation with Cysteine during Pregnancy Rescues Maternal Chronic Kidney Disease-Induced Hypertension in Male Rat Offspring: The Impact of Hydrogen Sulfide and Microbiota-Derived Tryptophan Metabolites.

Maternal chronic kidney disease (CKD) is linked to offspring hypertension. The gut microbiome and its tryptophan metabolites, nitric oxide (NO), and renin–angiotensin system (RAS) are closely related to the development of hypertension. Hydrogen sulfide (H2S) has shown an anti-hypertensive effect. Our objective was to test whether l- or d-cysteine supplementation in pregnancy can prevent hypertension programmed by maternal CKD in adult offspring and to explore the protective mechanisms. CKD was induced in pregnant Sprague Dawley rats by a 0.5% adenine diet for 3 weeks. l- or d-cysteine was supplemented at 8 mmol/kg body weight/day during pregnancy. Male offspring were sacrificed at the age of 12 weeks (n = 8 per group). Maternal CKD-induced hypertension was similarly prevented by l- or d-cysteine supplementation. The protective effects of l- and d-cysteine are related to reducing oxidative stress, rebalancing the RAS, and reshaping the gut microbiome. l-cysteine therapy protected adult offspring against hypertension and was associated with enhanced H2S production, restoration of NO bioavailability, enhancement of beneficial genera Oscillibacter and Butyricicoccus, depletion of indole-producing genera Alistipes and Akkermansia, and the reduction of several indole metabolites. d-cysteine treatment increased kynurenic acid, 3-hydroxykynurenine, and xanthurenic acid in the kynurenine pathway, decreased 5-hydroxytryptophan and serotonin in the serotonin pathway, and enriched genera Bacteroides and Odoribacter abundance. In summary, these results suggest that l- and d-cysteine protect against maternal CKD-induced offspring hypertension, likely by enhancing H2S production, modulating gut microbiota and its derived metabolites, and the restoration of NO and RAS.

Maternal overnutrition elevates offspring's blood pressure-Asystematic review and meta-analysis.

BackgroundMaternal overnutrition during pregnancy predisposes the offspring to cardiometabolic diseases.ObjectivesThis systematic review and meta‐analysis aimed to investigate the association between maternal overnutrition and offspring's blood pressure (BP) and the effect of offspring's obesity on this association.Data sourcesPubMed, EMBASE, Clinicaltrials.gov, CENTRAL.Study selection and data extractionHuman studies published in English before October 2021 were identified that presented quantitative estimates of association between maternal overnutrition just before or during pregnancy and the offspring's BP.SynthesisRandom‐effect model with the DerSimonian and Laird weighting method was used to analyse regression coefficients or mean differences.ResultsAfter selection, 17 observational studies (140,517 mother‐offspring pairs) were included. Prepregnancy body mass index (ppBMI) showed positive correlation with BP in offspring (regression coefficient for systolic: 0.38 mmHg per kg/m2, 95% confidence interval (CI) 0.17, 0.58; diastolic: 0.10 mmHg per kg/m2, 95% CI 0.05, 0.14). These indicate 1.9 mmHg increase in systolic and 0.5 mmHg increase in diastolic BP of offspring with every 5 kg/m2 gain in maternal ppBMI. Results on coefficients adjusted for offspring's BMI also showed association (systolic: 0.08 mmHg per kg/m2, 95% CI 0.04, 0.11; diastolic: 0.03 mmHg per kg/m2, 95% CI 0.01, 0.04). Independent from ppBMI, gestational weight gain (GWG) showed positive correlation with systolic BP (systolic BP: 0.05 mmHg per kg, 95% CI 0.01, 0.09), but not after adjustment for offspring's BMI. Mean systolic BP was higher in children of mothers with excessive GWG than in those of mothers with optimal GWG (difference: 0.65 mmHg, 95% CI 0.25, 1.05).ConclusionsIndependent from offspring's BMI, higher prepregnancy BMI may increase the risk for hypertension in offspring. The positive association between GWG and offspring's systolic BP is indirect via offspring's obesity. Reduction in maternal obesity and treatment of obesity in children of obese mothers are needed to prevent hypertension.

Elevated Expression of lncRNA MEG3 Induces Endothelial Dysfunction on HUVECs of IVF Born Offspring via Epigenetic Regulation.

Cardiovascular dysfunction in children born after in vitro fertilization (IVF) has been of great concern, the potential molecular mechanisms for such long-term outcomes are still unknown. Here, we found that systolic blood pressure was a little higher in IVF born offspring at 2 years old compared to those born after being naturally conceived. Besides, the expression level of maternally expressed gene 3 (MEG3) was higher in human umbilical vein endothelial cells (HUVECs) from IVF offspring than that in spontaneously born offspring. Pearson correlation test showed that MEG3 relative expression is significantly related to the children's blood pressure (Coefficient = 0.429, P = 0.0262). Furthermore, we found decreased expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) along with elevated expression of endothelial-1(ET1) in HUVECs from IVF offspring, accompanied by lower secretion of nitrite, VEGF, and higher secretion of ET1 in the umbilical cord serum of IVF offspring. Correlation analysis showed MEG3 expression highly correlated with ET1 and Nitrate concentration. With pyrosequencing technology, we found that elevated expression of MEG3 was the result of hypomethylation of the MEG3 promoter. Therefore, our results provide a potential mechanism addressing the high-risk of hypertension in IVF offspring via MEG3 epigenetic regulation.

Effect of intermittent fasting on cardiovascular parameters of young adult offspring of hypertensive parents

Background: Offspring of hypertensive parents have been reported to have alteration on their sympathovagal balance and have exaggerated response to stressful conditions. Many Christians observe a period of fasting at the beginning of every year, which imposes some stress on their bodies. Objective: This study aims to investigate the effect of 21-day intermittent fasting on some cardiovascular parameters in offspring of hypertensive and normotensive parents. Materials and Methods: Eighty young adults (20–28 years) were divided into equal number of male and female offspring of hypertensive and normotensive parents based on questionnaire. Their body weight, height, waist circumference (WC), body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded 1 week before the fasting period began and then weekly for 3 weeks, in which they fasted. Results: The weight, BMI, and WC reduced during fasting, but the reductions were not significant (P > 0.05). The SBP and DBP were higher in male offspring of hypertensive parents than all other groups. SBP was also significantly (P < 0.05) higher in males than females before fast and during fast. Fasting significantly reduced the SBP in the male offspring of both hypertensive and normotensive parents. The HR reduced in the females during fast but increased from a lower level in males to a value not significantly different from prefasting level. Conclusion: Fasting reduces the high SBP and DBP in male offspring of hypertensive parents, which is beneficial to their cardiovascular system.

Pathophysiological mechanisms of hypertension development induced by fructose consumption.

During the past several decades, there has been a dramatic increase in fructose consumption worldwide in parallel with epidemics of metabolic diseases. Accumulating evidence has suggested that excessive fructose consumption is extensively linked to an increase in blood pressure. A combined intake of high fructose and high salt induced salt-sensitive hypertension and maternal high-fructose consumption induced programmed hypertension in adult offspring. The underlying mechanisms of these two events are similar and complex. These mainly include activation of the intrarenal renin-angiotensin system, gut dysbiosis, enhanced oxidative stress, activation of nephron ion transporters, and dysregulation of T-lymphocytes. The major objective of this article is to review recent advances in these fields and suggest novel therapies targeting these mechanisms that have potentially beneficial effects on diet-associated hypertension.

Prenatal Chronic Hypoxia in Rats Leads to Insulin Resistance and Hypertension in Adult Offspring

Abstract Background To investigate the effects of chronic intrauterine hypoxia on insulin resistance, hypertension, and the correlation between them in adult offspring rats. Methods A total of 25 pregnant Sprague Dawley rats were randomly assigned into 4 prenatal chronic hypoxia (H) groups (10% ± 1% oxygen) and a control group (21% oxygen). The H groups were divided into whole (1–21 day), early (1–7 day), mid (8–14 day), and late (15–21 day) gestational hypoxia groups (H1, H2, H3, and H4, respectively) with pregnant rats being housed in a hypoxia box for 3 hours per day. Five male and 5 female offspring in each group were studied at 1 day, 3 months, and 6 months old. Blood pressure, fasting blood glucose, fasting serum insulin, and insulin resistance index were determined. Results The mean blood pressure of offspring rats in H groups was higher at 3 months, and further increased at 6 months old compared to the control group (P < 0.05). The fasting blood glucose and homeostasis model insulin resistance index (HOMA-IR) of male and female offspring in the whole pregnancy (H1) and early pregnancy (H2) hypoxia groups were significantly higher than those in the control group at 6 months (P < 0.05). Fasting blood glucose and HOMA-IR were positively correlated with mean blood pressure (P < 0.05). The renal mass index in H2 group was lower at 3 months, and further decreased at 6 months compared to controls (P < 0.05). The mRNA and protein levels of insulin receptor, insulin receptor substrate (IRS-1 and IRS-2) in the kidneys in hypoxia groups were significantly decreased at 6 months in H1 and H2 hypoxia groups when compared with controls (P < 0.05). Conclusions Chronic intrauterine hypoxia causes insulin resistance and hypertension in adult offspring rats through poor intrauterine growth environment, and insulin resistance is positively associated with hypertension.

Paternal long-term PM2.5 exposure causes hypertension via increased renal AT1R expression and function in male offspring.

Maternal exposure to fine particulate matter (PM2.5) causes hypertension in offspring. However, paternal contribution of PM2.5 exposure to hypertension in offspring remains unknown. In the present study, male Sprague-Dawley rats were treated with PM2.5 suspension (10 mg/ml) for 12 weeks and/or fed with tap water containing an antioxidant tempol (1 mM/L) for 16 weeks. The blood pressure, 24 h-urine volume and sodium excretion were determined in male offspring. The offspring were also administrated with losartan (20 mg/kg/d) for 4 weeks. The expressions of angiotensin II type 1 receptor (AT1R) and G-protein–coupled receptor kinase type 4 (GRK4) were determined by qRT-PCR and immunoblotting. We found that long-term PM2.5 exposure to paternal rats caused hypertension and impaired urine volume and sodium excretion in male offspring. Both the mRNA and protein expression of GRK4 and its downstream target AT1R were increased in offspring of PM2.5-exposed paternal rats, which was reflected in its function because treatment with losartan, an AT1R antagonist, decreased the blood pressure and increased urine volume and sodium excretion. In addition, the oxidative stress level was increased in PM2.5-treated paternal rats. Administration with tempol in paternal rats restored the increased blood pressure and decreased urine volume and sodium excretion in the offspring of PM2.5-exposed paternal rats. Treatment with tempol in paternal rats also reversed the increased expressions of AT1R and GRK4 in the kidney of their offspring. We suggest that paternal PM2.5 exposure causes hypertension in offspring. The mechanism may be involved that paternal PM2.5 exposure-associated oxidative stress induces the elevated renal GRK4 level, leading to the enhanced AT1R expression and its-mediated sodium retention, consequently causes hypertension in male offspring.

Maternal Hypertension and Hypertensive Disorders of Pregnancy Are Associated with Increased Risk of Hypertension in Offspring

Maternal Hypertension and Hypertensive Disorders of Pregnancy Are Associated with Increased Risk of Hypertension in Offspring

Abstract P224: Obesity Is Associated With Hypoxia At The Maternal-fetal Interface In A Mouse Model Of Superimposed Preeclampsia, BPH/5

Obesity impacts 1/3 of US adults. Maternal obesity significantly increases risk of adverse pregnancy outcomes, including preeclampsia (PE). Late-gestational hypertension and fetal growth restriction (FGR), hallmarks of PE, are observed spontaneously in BPH/5 mice. Similar to obese preeclamptic women, BPH/5 have increased visceral white adipose tissue (WAT) and are leptin resistant. We hypothesize that attenuation of maternal obesity and reduction of reproductive WAT in pregnant BPH/5 female mice will improve decidualization, placental development, and attenuate FGR. To test this hypothesis, pregnant C57 and BPH/5 female mice fed ad libitum (lib) and pair-fed (PF) BPH/5 female mice, beginning at day of copulatory plug detection, e0.5 (n=5/group), were utilized. Pair-feeding BPH/5 females the equivalent daily food intake of lean control ad lib fed C57 females reduced maternal WAT and circulating leptin in this model by e7.5 as well as reduced pro-inflammatory cytokines, Ptgs2 and IL-6, mRNA in the decidua. Therefore, we tested whether hypoxia-related genes, hypoxia inducible factor (Hif) 1α, heme oxygenase-1 (Ho-1), and stem cell factor (Scf), would be altered in the decidua of PF BPH/5 at e7.5. Using real time PCR, we found that e7.5 implantation sites from ad lib fed BPH/5 had a 1.5 to 2-fold increase in Hif1α, Ho-1, Scf, and VEGF mRNA (p<0.05) compared to C57 that was significantly reduced by PF. Furthermore, real time PCR for leptin (lep) mRNA showed a 6-fold increase in e7.5 implantation sites from ad lib fed BPH/5 versus C57 and lep along with lep receptor mRNA was reduced in PF BPH/5 (p<0.05). Therefore, PF BPH/5 pregnant mice have attenuated obesity and leptin in WAT, circulation, and e7.5 implantation sites that is associated with a reduction in markers of hypoxia at the maternal-fetal interface. Finally, BPH/5 PF litter sizes are significantly higher than ad lib fed, 6 vs 3.5, respectively (n=5-8; p<0.05) and symmetrical FGR is attenuated. In conclusion, maternal weight loss in BPH/5 beginning at conception may improve placental development by mitigating hypoxia at the maternal-fetal interface in this model. Future investigations are needed to determine this effect on the maternal hypertensive syndrome and offspring outcomes long-term.

Association of Maternal Hypothyroidism With Cardiovascular Diseases in the Offspring.

BackgroundNo previous study has examined the effect of maternal hypothyroidism on a broad spectrum of cardiovascular disease (CVD) endpoints in the offspring.MethodsA nationwide population-based cohort study based on the linkage of several Danish nationwide registries was conducted to explore whether maternal hypothyroidism is associated with offspring’s CVD. Altogether 1,041,448 singletons born between the 1st of January 1978 and the 31st of December 1998 were investigated from the age of 8 years to the 31st of December 2016. Exposure was maternal diagnosis of hypothyroidism across lifespan and the outcome of interest was a CVD diagnosis in the offspring. Cox regression models were performed to estimate the hazard ratios (HRs) of CVD.ResultsOffspring born to mothers with hypothyroidism had an increased risk of CVD (hazard ratios (HR)=1.23, 95% confidence interval (CI): 1.12-1.35), and of several subcategories of CVD including hypertension, arrhythmia, and acute myocardial infarction in offspring. The magnitude of association was the most pronounced in an exposure occur during pregnancy (HR=1.71, 95% CI: 1.10-2.67), which is consistent across all the subgroup analysis, including sibling analysis.ConclusionsMaternal hypothyroidism is associated with an increased risk of CVD in offspring. Thyroid hormone insufficiency during pregnancy may predominantly contribute to the observed associations; however, the effects of a shared genetic background and a time-stable familial environment/lifestyle factors cannot be excluded.

Perinatal Resveratrol Therapy to Dioxin-Exposed Dams Prevents the Programming of Hypertension in Adult Rat Offspring.

Exposure to environmental chemicals during pregnancy and lactation is a contributing factor in gut microbiota dysbiosis and linked to programming of hypertension. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic dioxin, induces toxic effects by mediating aryl hydrocarbon receptor (AHR). Resveratrol, a potent antioxidant with prebiotic properties, can possess high affinity for AHR and protect against TCDD-activated AHR attack. We examined whether perinatal resveratrol therapy prevents offspring hypertension programmed by maternal TCDD exposure and whether its beneficial effects are related to reshaping gut microbiota and antagonizing AHR-mediated T helper 17 (TH17) cells responses using a maternal TCDD exposure rat model. Pregnant Sprague-Dawley rats were given a weekly oral dose of TCDD 200 ng/kg for four doses (T), 50 mg/L of resveratrol in drinking water (CR), TCDD + resveratrol (TR), or vehicle (C) in pregnancy and lactation periods. Male offspring (n = 7–8/group) were sacrificed at the age of 12 weeks. Perinatal TCDD exposure caused elevated blood pressure in adult male offspring, which resveratrol supplementation prevented. Additionally, the TCDD-induced programming of hypertension is coincided with the activation of AHR signaling, TH17-induced renal inflammation, and alterations of gut microbiota compositions. Conversely, TCDD-mediated induction of AHR signaling and TH17 responses were restored by maternal resveratrol supplementation. Furthermore, maternal resveratrol supplementation prevented the programming of hypertension and was related to increased genera Bacteroides, ASF356, and Lachnoclostridium. Taken together, these results suggest that the interplay between gut microbiota, AHR-mediated TH17 responses, and renal inflammation in the gut and kidneys may play an important role in the action of resveratrol against TCDD-induced programming of hypertension.

Inhibition of Maternal c-Src Ameliorates the Male Offspring Hypertension by Suppressing Inflammation and Neurotransmitters in the Paraventricular Nucleus.

Long-term maternal salt intake induces the hypertension in offspring. Numerous studies have also indicated that high-salt diet causes the inflammation and an imbalance in neurotransmitters in the paraventricular nucleus (PVN) which increases the blood pressure and sympathetic activity. This study aimed to explore whether maternal salt intake induces hypertension in their male offspring by increasing the inflammation and changing the neurotransmitters balance in the paraventricular nucleus of offspring. This study includes two parts: Part I to explore the effect of high-salt diet on pregnant rats and the changes in inflammation and neurotransmitters in their male offspring PVN; Part II to reveal the influence on their offspring of bilateral PVN infusion of c-Src inhibitor dasatinib (DAS)in pregnant rats fed a high-salt diet. Maternal high-salt diet intake during copulation, pregnancy, and lactation impacted the offspringmean arterial pressure (MAP) and elevated the offspring PVN levels of p-Src, proinflammatory cytokines, and excitatory neurotransmitters. Bilateral PVN infusion of a c-Src inhibitor combined with maternal high-salt diets decreased MAP in the offspring. The infusion was also shown to suppress the Src-induced MAPK/NF-κB signaling pathway (p38 MAPK, JNK, Erk1/2), which attenuates inflammatory reactions. Finally, bilateral PVN infusion of the Src inhibitor in pregnant rat with high-salt diets improved the levels of inhibitory neurotransmitters in offspring PVN, which restored the excitatory-inhibitory neurotransmitter balance in male offspring. High-salt diets increase sympathetic activity and blood pressure in adult offspring, probably by activating the c-Src/MAPKs/NF-κB signaling pathway-induced inflammation. Moreover, NF-κB disrupts the downstream excitatory-inhibitory neurotransmitter balance in the PVN of male offspring.

Leptin and Melanocortin Signaling Mediates Hypertension in Offspring From Female Rabbits Fed a High-Fat Diet During Gestation and Lactation.

Maternal high-fat diet in rabbits leads to hypertension and elevated renal sympathetic nerve activity (RSNA) in adult offspring but whether this is due to adiposity or maternal programming is unclear. We gave intracerebroventricular (ICV) and ventromedial hypothalamus (VMH) administration of leptin-receptor antagonist, α-melanocyte-stimulating hormone (αMSH), melanocortin-receptor antagonist (SHU9119), or insulin-receptor (InsR) antagonist to conscious adult offspring from mothers fed a high-fat diet (mHFD), control diet (mCD), or mCD offspring fed HFD for 10d (mCD10d, to deposit equivalent fat but not during development). mHFD and mCD10d rabbits had higher mean arterial pressure (MAP, +6.4 mmHg, +12.1 mmHg, p < 0.001) and RSNA (+2.3 nu, +3.2 nu, p < 0.01) than mCD, but all had similar plasma leptin. VMH leptin-receptor antagonist reduced MAP (−8.0 ± 3.0 mmHg, p < 0.001) in mCD10d but not in mHFD or mCD group. Intracerebroventricular leptin-receptor antagonist reduced MAP only in mHFD rabbits (p < 0.05). Intracerebroventricular SHU9119 reduced MAP and RSNA in mHFD but only reduced MAP in the mCD10d group. VMH αMSH increased RSNA (+85%, p < 0.001) in mHFD rabbits but ICV αMSH increased RSNA in both mHFD and mCD10d rabbits (+45%, +51%, respectively, p < 0.001). The InsR antagonist had no effect by either route on MAP or RSNA. Hypothalamic leptin receptor and brain-derived neurotrophic factor (BDNF) mRNA were greater in mHFD compared with mCD rabbits and mCD10d rabbits. In conclusion, the higher MAP in mHFD and mCD10d offspring was likely due to greater central leptin signaling at distinct sites within the hypothalamus while enhanced melanocortin contribution was common to both groups suggesting that residual body fat was mainly responsible. However, the effects of SHU9119 and αMSH on RSNA pathways only in mHFD suggest a maternal HFD may program sympatho-excitatory capacity in these offspring and that this may involve increased leptin receptor and BDNF expression.

Maternal Garlic Oil Supplementation Prevents High-Fat Diet-Induced Hypertension in Adult Rat Offspring: Implications of H2S-Generating Pathway in the Gut and Kidneys.

Perinatal high-fat (HF) diet induces hypertension in adult offspring. Garlic, a naturally dietary source of Hydrogen sulfide (H2 S) donor, has been shown benefits in hypertension. The article examines whether maternal garlic oil supplementation can prevent hypertension induced by HF diet and elucidate its protective effects. Pregnant rats are given either a normal diet or HF diet. Rat dams are given garlic oil or vehicle daily by oral gavage at 100mg kg-1 day-1 during pregnancy and lactation. Male offspring are sacrificed at 16 weeks of age. Garlic oil supplementation during pregnancy and lactation protected against hypertension induced by HF diet in adult male offspring. The beneficial effects of garlic oil are associated with increased renal mRNA expression and activity of H2 S-generating enzymes, increased NO bioavailability, increased plasma short chain fatty acid levels, and alterations of gut microbiota composition. Garlic oil supplementation increases abundance of genus Lactobacillus, but decreases genera Turicibacter and Staphylococcus. The data reveals associations between H2 S-generating pathway in the gut and kidneys, NO system, gut microbiota, and microbiota-derived metabolites in hypertension induced by HF intake and provide insight to garlic oil as a hypertension reprogramming strategy for further translational research.

Perinatal Resveratrol Therapy Prevents Hypertension Programmed by Maternal Chronic Kidney Disease in Adult Male Offspring: Implications of the Gut Microbiome and Their Metabolites.

The gut microbiota plays a critical role in kidney disease and hypertension; however, whether maternal chronic kidney disease (CKD)-induced offspring hypertension is associated with alterations of the microbiota and microbial metabolites remains elusive. Using rat as an animal model, we conducted a maternal adenine-induced CKD model to examine whether adult male offspring develop hypertension and kidney disease. As resveratrol has antioxidant and prebiotic properties, we also aimed to elucidate whether its use in pregnancy and lactation can benefit hypertension programmed by maternal CKD via mediation of the gut microbiota and oxidative stress. Female Sprague-Dawley rats received regular chow (C) or chow supplemented with 0.5% adenine (CKD) from 3 weeks before pregnancy until lactation. One group of the adenine-induced CKD pregnant rats received resveratrol (R; 50 mg/L) in drinking water during gestation and lactation. Male offspring were divided into three groups: C, CKD, and CKD+R. The microbial metabolites analyzed were short chain fatty acids (SCFAs) in feces and trimethylamine (TMA)/trimethylamine N-oxide (TMAO) in plasma. We found perinatal resveratrol therapy protected against maternal CKD-induced hypertension in adult male offspring. The overall microbial compositions and diversity of bacterial community in the three groups were different. Resveratrol therapy increased α-diversity, decreased the Firmicutes to Bacteroidetes ratio, and increased the abundance of the genera Lactobacillus and Bifidobacterium. Perinatal resveratrol therapy increased plasma TMA levels but decreased the plasma TMAO-to-TMA ratio. Although resveratrol had negligible effect on fecal concentrations of SCFAs, it increased G-protein coupled receptor-41 (GPR41) protein levels in the offspring’s kidneys. Additionally, resveratrol therapy increased plasma levels of L-arginine and the L-arginine-to-ADMA ratio (AAR), and decreased oxidative stress. Overall, the protective effects of resveratrol against programmed hypertension are related to gut microbiome remodeling, including an increased abundance of beneficial microbes, mediation of the TMA-TMAO pathway, and alterations of SCFA receptors. Our results highlighted that targeting the microbiome and their metabolites might be potential therapeutic strategies to prevent maternal CKD-induced adverse pregnancy and offspring outcomes.