Hypertension In Offspring Research Articles

Whether AICAR in Pregnancy or Lactation Prevents Hypertension Programmed by High Saturated Fat Diet: A Pilot Study.

High consumption of saturated fats links to the development of hypertension. AMP-activated protein kinase (AMPK), a nutrient-sensing signal, is involved in the pathogenesis of hypertension. We examined whether early intervention with a direct AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) during pregnancy or lactation can protect adult male offspring against hypertension programmed by high saturated fat consumption via regulation of nutrient sensing signals, nitric oxide (NO) pathway, and oxidative stress. Pregnant Sprague–Dawley rats received regular chow or high saturated fat diet (HFD) throughout pregnancy and lactation. AICAR treatment was introduced by intraperitoneal injection at 50 mg/kg twice a day for 3 weeks throughout the pregnancy period (AICAR/P) or lactation period (AICAR/L). Male offspring (n = 7–8/group) were assigned to five groups: control, HFD, AICAR/P, HFD + AICAR/L, and HFD + AICAR/P. Male offspring were killed at 16 weeks of age. HFD caused hypertension and obesity in male adult offspring, which could be prevented by AICAR therapy used either during pregnancy or lactation. As a result, we demonstrated that HFD downregulated AMPK/SIRT1/PGC-1α pathway in offspring kidneys. In contrast, AICAR therapy in pregnancy and, to a greater extent, in lactation activated AMPK signaling pathway. The beneficial effects of AICAR therapy in pregnancy is related to restoration of NO pathway. While AICAR uses in pregnancy and lactation both diminished oxidative stress induced by HFD. Our results highlighted that pharmacological AMPK activation might be a promising strategy to prevent hypertension programmed by excessive consumption of high-fat food.

Increased blood pressure and impaired endothelial function after accelerated growth in IVF/ICSI children.

STUDY QUESTIONWhat is the effect of growth velocity (height and weight) in early infancy on metabolic end-points and endothelial function in children born after ART?SUMMARY ANSWERNeonatal, infant and childhood growth is positively related to blood pressure in 9-year-old IVF/ICSI offspring, while growth in childhood was negatively associated with endothelial function.WHAT IS KNOWN ALREADYOffspring of pregnancies conceived after ART are at risk for later cardiometabolic risk factors. It is well established that early growth is related to numerous later cardiometabolic risk factors such as high blood pressure. This concept is known as the Developmental Origin of Health and Disease theory.STUDY DESIGN, SIZE, DURATIONThe relation between early growth and later cardiometabolic risk profile was studied in the MEDIUM-KIDS study, a prospective observational cohort study in children born after an IVF/ICSI treatment. In 131 children (48.1% males) at the average age of 9.4 years, cardiometabolic outcomes were assessed and growth data from birth until age 9 years were collected from child welfare centers.PARTICIPANTS/MATERIALS, SETTINGS, METHODSThe following cardiometabolic outcomes were assessed: blood pressure, skinfolds, lipid spectrum, hair cortisone and glucose and insulin levels. Data on maximum skin perfusion after transdermal delivery of acetylcholine as a measure of endothelial function were collected.Growth charts were obtained electronically from child welfare centers, which offer free consultations and vaccinations to all Dutch children. At these centers, height and weight are recorded at predefined ages. Growth was defined as z-score difference in weight between two time points. Multivariable linear regression analysis was used to model the relation between growth and cardiometabolic outcomes. The following growth windows were –studied simultaneously in each model: 0–1 month, 1–3 months, 3–6 months, 6–11 months, 11–24 months and 2–6 years. The model was adjusted for height growth in all intervals except for 0–1 month.MAIN RESULTS AND THE ROLE OF CHANCEIn multivariable linear regression analyses, multiple growth windows were positively associated with blood pressure, for example growth from 2–6 years was significantly related to systolic blood pressure: B = 4.13, P = 0.005. Maximum skin perfusion after acetylcholine was negatively associated with height-adjusted weight gain from 2 to 6 years: B = −0.09 (log scale), P = 0.03. Several growth windows (weight 1–3 months, 3–6 months, 6–11 months, 11–24 months, 2–6 years) were positively linked with total adiposity. Lipids, glucose tolerance indices and cortisone were not related to growth.LIMITATIONS, REASONS FOR CAUTIONThis study is of modest size and of observational nature, and we did not include a control group. Therefore, we cannot assess whether the observed associations are causal. It is also not possible to analyze if our observations are specific for, or exacerbated in, the ART population. Ideally, a control group of naturally conceived siblings of IVF/ICSI children should simultaneously be studied to address this limitation and to assess the impact of the ART procedure without the influence of parental (subfertility) characteristics.WIDER IMPLICATIONS OF THE FINDINGSThe results of this study contribute to our understanding of the reported increased risk for hypertension in ART offspring. We speculate that early, accelerated growth may be involved in the reported increased risk for hypertension in ART offspring, with endothelial dysfunction as a possible underlying mechanism. However, additional research into the mechanisms involved is required.STUDY FUNDING/COMPETING INTEREST(S)The study was financially supported by the March of Dimes, grant number #6-FY13-153. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the paper. The authors have no conflict of interest to declare.TRIAL REGISTRATION NUMBERNTR4220

Oral administration of Lactobacillus fermentum post-weaning improves the lipid profile and autonomic dysfunction in rat offspring exposed to maternal dyslipidemia.

Maternal dyslipidemia alters the gut microbiota composition and contributes to the development of arterial hypertension (AH) in offspring. Here, we evaluated the effects of a new Lactobacillus fermentum probiotic formulation given post-weaning on cardiometabolic parameters and gut microbiota in male and female rat offspring from dams exposed to maternal dyslipidemia during pregnancy and lactation. Wistar rats (n = 14) were fed with a control diet (CTL = 7) or a dyslipidemic diet (DLP = 7) during pregnancy and lactation. After weaning, male and female offspring received a standard diet up to 90 days of life. Rats were allocated into three groups: CTL group + saline solution (n = 14); DLP group + saline solution (n = 14) and DLP group receiving a probiotic cocktail (n = 14). A vehicle or probiotic formulation containing L. fermentum 139, L. fermentum 263 and L. fermentum 296 (ratio 1 : 1 : 1, 1 × 109 CFU mL-1) was administered daily by oral gavage for 8 weeks. The intervention with the probiotic formulation of L. fermentum in male and female offspring reduced total cholesterol (TC) and increased HDL-c, but did not affect the insulin resistance induced by maternal dyslipidemia. Additionally, the male and female rats that received the probiotic formulation of L. fermentum demonstrated improvement in fecal Lactobacillus sp. counts, blood pressure and sympathetic tone, without affecting baroreflex modulation. The probiotic formulation containing L. fermentum improved the lipid profile and autonomic dysfunction in male and female offspring exposed to maternal dyslipidemia.

Sympathetic activation of splenic T-lymphocytes in hypertension of adult offspring programmed by maternal high fructose exposure.

Whereas neuroimmune crosstalk between the sympathetic nervous system (SNS) and immune cells in the pathophysiology of hypertension is recognized, the exact effect of SNS on T-lymphocyte in hypertension remains controversial. This study assessed the hypothesis that excitation of the SNS activates splenic T-lymphocytes through redox signaling, leading to the production of pro-inflammatory cytokines and the development of hypertension. Status of T-lymphocyte activation, reactive oxygen species (ROS) production and pro-inflammatory cytokines expression in the spleen were examined in a rodent model of hypertension programmed by maternal high fructose diet (HFD) exposure. Maternal HFD exposure enhanced SNS activity and activated both CD4+ and CD8+ T-lymphocytes in the spleen of young offspring, compared to age-matched offspring exposed to maternal normal diet (ND). Maternal HFD exposure also induced tissue oxidative stress and expression of pro-inflammatory cytokines in the spleen of HFD offspring. All those cellular and molecular events were ameliorated following splenic nerve denervation (SND) by thermoablation. In contrast, activation of splenic sympathetic nerve by nicotine treatment resulted in the enhancement of tissue ROS level and activation of CD4+ and CD8+ T-cells in the spleen of ND offspring; these molecular events were attenuated by treatment with a ROS scavenger, tempol. Finally, the increase in systolic blood pressure (SBP) programmed in adult offspring by maternal HFD exposure was diminished by SND, whereas activation of splenic sympathetic nerve increased basal SBP in young ND offspring. These findings suggest that excitation of the SNS may activate splenic T-lymphocytes, leading to hypertension programming in adult offspring induced by maternal HFD exposure. Moreover, tissue oxidative stress induced by the splenic sympathetic overactivation may serve as a mediator that couples the neuroimmune crosstalk to prime programmed hypertension in HFD offspring.

Atenolol increases dental mineralization in male offspring of treated hypertensive rats and normotensive rats.

This study evaluates how atenolol affects dental mineralization in offspring of female spontaneously hypertensive rats (fSHR) and normotensive Wistar rats (fW). fSHR and fW were treated with atenolol (100 mg/Kg/day, orally) during pregnancy and lactation. Non-treated fSHR and fW were the control groups. Enamel and dentin hardness were analyzed (Knoop, 15 g load, 10s) in mandibular incisor teeth (IT) and molar teeth (MT) obtained from the male offspring of atenolol-treated and non-treated fWistar and fSHR. Data were analyzed by ANOVA, followed by Tukey post hoc test (p < 0.05). Atenolol reduced the arterial blood pressure (SBP) in fSHR, but it did not change the SBP in fW. The offspring of non-treated fSHR had lower enamel (IT and MT) and dentin (IT) hardness than the offspring of non-treated fW (p < 0.05). Atenolol increased enamel and dentin hardness in the IT obtained from the offspring of fSHR and fW (p<0.05), but the offspring of fSHR presented higher values (p < 0.05). Atenolol did not alter enamel width in the IT obtained from any of the groups, but it increased enamel and dentin hardness in the IT obtained from the offspring of fSHR and fW. Atenolol affected the IT obtained from the offspring of fSHR. Atenolol increased only enamel hardness in the MT obtained from the offspring of fW. In conclusion, maternal hypertension reduces tooth hard tissues, and treatment with atenolol increases tooth hardness in male offspring of hypertensive and normotensive female rats.

Hypertension Programmed by Perinatal High-Fat Diet: Effect of Maternal Gut Microbiota-Targeted Therapy.

Hypertension can originate in early life caused by perinatal high-fat (HF) consumption. Gut microbiota and their metabolites short chain fatty acids (SCFAs), trimethylamine (TMA), and trimethylamine N-oxide (TMAO) are involved in the development of hypertension. Despite the beneficial effects of prebiotic/probiotic on human health, little is known whether maternal use of prebiotics/probiotics could protect offspring against the development of hypertension in adulthood. We investigated whether perinatal HF diet-induced programmed hypertension in adult offspring can be prevented by therapeutic uses of prebiotic inulin or probiotic Lactobacillus casei during gestation and lactation. Pregnant Sprague–Dawley rats received regular chow or HF diet (D12331, Research Diets), with 5% w/w long chain inulin (PRE), or 2 × 108 CFU/day Lactobacillus casei via oral gavage (PRO) during pregnancy and lactation. Male offspring (n = 8/group) were assigned to four groups: control, HF, PRE, and PRO. Rats were sacrificed at 16 weeks of age. Maternal prebiotic or probiotic therapy prevents elevated blood pressure (BP) programmed by perinatal HF consumption. Both prebiotic and probiotic therapies decreased the Firmicutes to Bacteroidetes ratio and renal mRNA expression of Ace, but increased abundance of genus Lactobacillus and Akkermansia. Additionally, prebiotic treatment prevents HF-induced elevation of BP is associated with reduced fecal propionate and acetate levels, while probiotic therapy restored several Lactobacillus species. Maternal probiotic or prebiotic therapy caused a reduction in plasma TMAO level and TMAO-to-TMA ratio. The beneficial effects of prebiotic or probiotic therapy on elevated BP programmed by perinatal HF diet are relevant to alterations of microbial populations, modulation of microbial-derived metabolites, and mediation of the renin-angiotensin system. Our results cast a new light on the use of maternal prebiotic/probiotic therapy to prevent hypertension programmed by perinatal HF consumption. The possibility of applying gut microbiota-targeted therapies as a reprogramming strategy for hypertension warrants further clinical translation.

Blockade of angiotensin-converting enzyme or tumor necrosis factor-α reverses maternal high-fat diet-induced sensitization of angiotensin II hypertension in male rat offspring.

Maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular diseases in adult offspring. Our previous study demonstrated that maternal HFD enhances pressor responses to ANG II or a proinflammatory cytokine (PIC), which is associated with increased expression of brain renin-angiotensin system (RAS) components and PICs in adult offspring. The present study further investigated whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor-α (TNF-α) blocks sensitization of ANG II hypertension in offspring of HFD dams. All offspring were bred from dams with normal fat diet (NFD) or HFD starting two weeks before mating and maintained until weaning of the offspring. Then the weaned offspring were treated with an ACE inhibitor (captopril) or a TNF-α inhibitor (pentoxifylline) in the drinking water through the end of testing with a slow-pressor dose of ANG II. RT-PCR analyses of the lamina terminalis and paraventricular nucleus revealed upregulation of mRNA expression of several RAS components and PICs in male offspring of HFD dams when compared with age-matched offspring of NFD dams. The enhanced gene expression was attenuated by blockade of either RAS or PICs. Likewise, ANG II administration produced an augmented pressor response in offspring of HFD dams. This was abolished by either ACE or TNF-α inhibitor. Taken together, this study provides mechanistic evidence and a therapeutic strategy that systemic inhibition of the RAS and PICs can block maternal HFD-induced sensitization of ANG II hypertension, which is associated with attenuation of brain RAS and PIC expression in offspring.

Stimulation of the ACE2/Ang-(1-7)/Mas axis in hypertensive pregnant rats attenuates cardiovascular dysfunction in adult male offspring.

The aim of this study was to investigate whether treatment with diminazene aceturate (DIZE), a putative ACE2 activator, or with angiotensin-(1-7) during pregnancy could attenuate the development of cardiovascular dysfunction in the adult offspring of spontaneously hypertensive rats (SHRs). For this, pregnant SHRs received DIZE or Ang-(1-7) throughout gestation. The systolic blood pressure (SBP) was measured in the male offspring from the 6th to16th weeks of age by tail-cuff plethysmography. Thereafter, the left ventricular contractile function and coronary reactivity were evaluated by the Langendorff technique. Samples of the left ventricles (LVs) and kidneys were collected for histology and western blot assay in another batch of adult rat offspring. Maternal treatment with DIZE or Ang-(1-7) during pregnancy attenuated the increase in SBP in adult offspring. In addition, both DIZE and Ang-(1-7) treatments reduced the cardiomyocyte diameter and fibrosis deposition in the LV, and treatment with Ang-(1-7) also reduced the fibrosis deposition in the kidneys. Maternal treatment with DIZE, as well as Ang-(1-7), improved the coronary vasodilation induced by bradykinin in isolated hearts from adult offspring. However, no difference was observed in the contractile function of the LVs of these animals. The expression levels of AT1 and Mas receptors, ACE, ACE2, SOD, and catalase in the LV were not modified by maternal treatment with Ang-(1-7), but this treatment elicited a reduction in AT2 expression. These data show that treatment with DIZE or Ang-(1-7) during gestation promoted beneficial effects of attenuating hypertension and cardiac remodeling in adult offspring.

Maternal Exposure to Bisphenol A Combined with High-Fat Diet-Induced Programmed Hypertension in Adult Male Rat Offspring: Effects of Resveratrol.

Maternal exposure to endocrine disrupting chemicals (EDCs) and a high-fat intake may induce the developmental programming of hypertension in adult offspring. Bisphenol A (BPA) is one of the most commonly environmental EDCs. As the nitric oxide (NO) and aryl hydrocarbon receptor (AHR) signaling pathways both contribute to the pathogenesis of hypertension, we evaluated whether resveratrol, an antioxidant and an AHR antagonist, can prevent hypertension programmed by a maternal BPA and HF diet. Sixteen-week-old male rat offspring were assigned to six groups (n = 8 per group): Control, HF (D12331, Research Diets), BPA (50 μg/kg/day), HF + BPA, BPA + R (resveratrol 50mg/L in drinking water throughout pregnancy and lactation), and HF + BPA + R. Maternal BPA exposure exacerbated hypertension programmed by HF consumption in adult male offspring, which was protected by maternal resveratrol therapy. The BPA and HF diet synergistically induced oxidative stress in offspring kidneys, which resveratrol treatment prevented. We observed that HF + BPA-induced programmed hypertension was associated with a decreased NO bioavailability, increased oxidative stress, and an activated AHR signaling pathway. The beneficial effects of resveratrol are relevant to restoring NO bioavailability, reducing oxidative stress, and antagonizing the AHR signaling pathway. Our results cast a new light on resveratrol as a reprogramming strategy to protect against hypertension programmed by combined BPA and HF exposure, but this strategy has yet to be translated into clinical applications.

Abstract 015: Maternal High Blood Pressure Control Persistently Alters Gut-Brain Communication and Attenuates Hypertension of Offspring

Objective: Evidence suggests involvement of a dysfunctional gut-brain axis in hypertension. Maternal-fetal cross-talk is implicated in the long-term control of hypertension of offspring. Therefore, we tested the hypothesis that maternal factors influence gut-brain axis impacting hypertension in offspring. Methods: Pregnant female spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats, were treated with captopril (CAP) water (100 mg/kg/day) or sterile water throughout pregnancy and lactation. At weaning, the pups from dams drinking sterile water were continued until age 12 weeks. The pups from dams drinking CAP water were divided into two groups: offspring continuously drinking CAP and offspring withdrawn from CAP, then drinking sterile water until age 12 weeks (N=8-11/group). Results: Compared with SHR, maternal exposure of SHR to CAP lowered systolic BP in offspring at weaning (Δ=24mmHg, P&lt;0.05). This was associated with amelioration of gut inflammation (decreased Cd3 by 2.8-fold, P&lt;0.01) and permeability (increased Tjp1 by 4.3-fold, P&lt;0.01; Ocln increased by 2.8-fold, P&lt;0.01). At 12 week-old, SHR offspring exposed to maternal CAP demonstrated persistent decreased systolic BP (Δ=25mmHg, P&lt;0.01), increased microbial Shannon diversity (Δ=1.25, P&lt;0.001), altered β diversity, and growth of beneficial bacterial genera, compared with SHR (increased Coprococcus by 41-fold, P&lt;0.001; Oscillospira by 4.9-fold, P&lt;0.01; Roseburia by 83-fold, P&lt;0.001; Mucispirillum by 26-fold, P&lt;0.01). Decreases in activated microglia numbers per area (Δ=2.8, P&lt;0.05) and neuroinflammation (decreased Tnf by 2.4-fold, P&lt;0.001; Il1b by 2.7-fold, P&lt;0.05) and improvement of gut inflammation ( Cd3 decreased by 1.8-fold, P&lt;0.01) and permeability (increased Tjp1 by 2.2-fold, P&lt;0.1; Ocln by 1.8-fold, P&lt;0.1) were also observed in these SHR offspring with maternal CAP, compared with SHR. These improvements were also found in the SHR with continuous CAP. Conclusion: Maternal decrease of BP by CAP improves dysregulated gut-brain axis in SHR offspring and long-term lowering of BP. Thus, it provides conceptual support that targeting of the gut-brain axis via the mother may be a relevant strategy for the control of hypertension in the offspring.

Abstract P3041: Maternal Hypertension Sensitizes Post Weaning High Fat Diet Elicited Hypertension in Adult Offspring

Our previous studies showed that maternal hypertension sensitizes angiotensin (ANG) II-induced hypertension and this sensitization is associated with upregulation of renin-angiotensin system (RAS) components and proinflammatory cytokines (PICs) in the brain cardiovascular nuclei. In this study, we investigated whether the offspring from mothers with maternal hypertension had a sensitized hypertensive response elicited by high-fat diet (HFD) feeding for 12 weeks beginning from the time of weaning. In both male and female offspring, basal mean arterial pressure (MAP) in normal-fat diet (NFD) feeding offspring of either normotensive (NT; males, 112.3±2.2; females, 109.0±1.5 mmHg) or hypertensive (HT; males 112.4±1.0; females 108.4±1.3 mmHg) dams were comparable. HFD feeding significantly elevated MAP in both male and female offspring. However, the increases in MAP were greater in offspring of HT dams (males, 128.0±2.3 mmHg; females, 121.0±1.8 mmHg) than that in the offspring of NT dams (males, 120.8±1.4 mmHg; females, 115.3±1.2 mmHg). Ganglionic blockade (hexamethonium, ip) produced a greater reduction fall in MAP only in male HFD-fed offspring when compared to NFD-fed offspring of either NT dams (-45.2±3.4 vs. -20.9±4.1 mmHg) or HT dams (-41.2±6.7 vs. -26.6±2.5 mmHg), suggesting that HFD feeding elicited an increased sympathetic tone in males, but not in females. In lamina terminalis tissues, RT-PCR analyses revealed that HFD feeding in both male and female offspring of HT dams led to a significant increase in mRNA expression of several components of the RAS and PICs (males, leptin, ACE, NOX2 and TNF-α; females, leptin, AT1R, NOX2 and TNF-α). However, maternal hypertension resulted in a significant increase in mRNA expression of leptin and AT1R only in male offspring fed NFD when compared with NFD offspring of NT dams. The results indicate that maternal hypertension sensitized HFD-elicited HT in both male and female adult offspring, but in a sex-specific manner associated with altered sympathetic tone and expression of RAS components and PICs in the brain.

Clinical Implications

Clinical Implications

Exercise during pregnancy enhances vascular function via epigenetic repression of CaV1.2 channel in offspring of hypertensive rats

AimsStudies suggest that cardiovascular function in offspring can be epigenetically programmed by environmental changes during pregnancy. CaV1.2 channel plays a major role in the regulation of the vascular tone. This study investigated the effects and underlying mechanisms of exercise during pregnancy on CaV1.2 channel functional remodeling in hypertensive offspring. Main methodsExercise groups were subjected to swimming at the first day of pregnancy and on a regular schedule thereafter for 3 weeks. Their offspring (6-month-old, male) were tested for baseline blood pressure, cardiovascular response, and vascular tone of the mesenteric artery. Mesenteric artery smooth muscle cells were taken to study the whole-cell current of the CaV1.2 channel. Western blotting, RT-PCR and DNA bisulfite sequencing PCR were performed to study the protein, mRNA expression and DNA methylation of the CaV1.2 channel α1C subunit. Key findingsExercise during pregnancy reduced the pressor response to norepinephrine and Bay K8644, and the depressor response to nifedipine in offspring of hypertensive rats. The level of the CaV1.2 channel in norepinephrine-induced vasoconstrictions decreased, and the whole-cell current of the CaV1.2 channel declined in the SHR-EX group. Further studies found that exercise during pregnancy reduced the protein and mRNA expression of the CaV1.2 channel α1C subunit and upregulated DNA methylation of the Cacna1c gene promoter region in the hypertensive offspring. SignificanceThese data suggest that exercise during pregnancy improves vascular functional remodeling in offspring of hypertensive rats, downregulating the CaV1.2 channel function and protein expression, a change that is most likely caused by DNA methylation.

Effect of sex on glomerular filtration rate in programmed rats by prenatal dexamethasone.

We have previously demonstrated that dexamethasone administered to pregnant rats during specific times during gestation results in a reduction in glomerular number and hypertension in offspring at 2 and 6 months of age. In this study, we examined the effect of prenatal dexamethasone administered daily on days 15 and 16 of gestation in male and female offspring after 1 year of age on glomerular filtration rate. The prenatal dexamethasone male group had a higher systolic blood pressure than the vehicle male group. Females had lower systolic blood pressures than the males and prenatal dexamethasone did not affect blood pressure in female offspring. Prenatal dexamethasone resulted in a reduction in glomerular filtration rate in male but not in female rats. When corrected for body weight, the control male rats had a lower glomerular filtration rate than the control female rats. Males had greater protein excretion than females and prenatal dexamethasone increased the protein excretion only in male rats. Glomerulosclerosis was also greater in male rats than females but was not affected by prenatal dexamethasone. In summary, male rats appear to have evidence of a decline in glomerular filtration rate after 1 year of age and prenatal dexamethasone programs an accelerated decline in glomerular filtration rate in male but not in female offspring.

Prenatal cold exposure causes hypertension in offspring by hyperactivity of the sympathetic nervous system.

Environmental temperature plays a role in the variation of blood pressure. Maternal cold stress could affect the physiological phenotype of the offspring, including blood pressure elevation. In the present study, we found that adult offspring of dams exposed to cold have increased systolic and diastolic blood pressure, and decreased urine volume and sodium excretion, accompanied by increased heart rate and heart rate variability, secondary to increased activity of the sympathetic nervous system. Renal denervation or adrenergic receptor blockade decreased blood pressure and increased sodium excretion. The increase in peripheral sympathetic nerve activity can be ascribed to the central nervous system because administration of clonidine, a centrally acting α2 adrenergic receptor agonist, lowered blood pressure to a greater degree in the prenatal cold-exposed than control offspring. Moreover, these prenatal cold-exposed offspring had hypothalamic paraventricular nucleus (PVN) disorder because magnetic resonance spectroscopy showed decreased N-acetylaspartate and increased choline and creatine ratios in the PVN. Additional studies found that prenatal cold exposure impaired the balance between inhibitory and excitatory neurons. This led to PVN overactivation that was related to enhanced PVN-angiotensin II type 1 (AT1) receptor expression and function. Microinjection of the AT1 receptor antagonist losartan in the PVN lowered blood pressure to a greater extent in prenatal cold-exposed that control offspring. The present study provides evidence for overactive peripheral and central sympathetic nervous systems in the pathogenesis of prenatal cold-induced hypertension. Central AT1 receptor blockade in the PVN may be a key step for treatment of this type hypertension.

Epigenetic alteration of Rho guanine nucleotide exchange Factor 11 (ARHGEF11) in cord blood samples in macrosomia exposed to intrauterine hyperglycemia

Background: Macrosomia at birth is associated with maternal hyperglycemia and leads to subsequent susceptibility to obesity, abnormal glucose metabolism, hypertension, and dyslipidemia in offspring. Epigenetic reprogramming has been reported to be involved in the development of human diseases caused by suboptimal environmental or nutritional factors. The study was aiming to explore epigenetic mechanism influences on macrosomic infants exposed to intrauterine hyperglycemia. We performed a genome-wide analysis of DNA methylation in cord blood from macrosomic infants born to women with gestational diabetes in order to identify genes related to fetal growth or early adipose tissue development.Methods: To analyze the epigenetic patterns in umbilical cord blood in gestational diabetes mellitus (GDM), we collected umbilical cord blood from women with GDM (mean pregestational BMI of 24.4 kg/m2 and mean neonatal birth weight of 4366 g) and normal glucose-tolerant women (mean pregestational BMI of 19.8 kg/m2 and mean neonatal birth weight of 3166 g). Differentially methylated genes in the GDM group were identified using the Infinium HumanMethylation450 BeadChip array.Results: A total of 1251 genes were differentially methylated compared to the controls (p < .01). The methylation microarray data showed that two specific CpG sites (cg12604331 and cg08480098) in the gene body of ARHGEF11 were significantly hypomethylated in the cord blood in macrosomic infants. Altered DNA methylation levels of ARHGEF11 were negatively correlated with glucose levels and neonatal birth weight.Conclusions: Exposure to adverse intrauterine environments can alter fetal development, such as by affecting the nutritional status of the fetus. Such exposure can also result in significant epigenetic modifications, including DNA methylation, which could serve as a potential marker for nutrition and metabolic conditions at the neonatal stage or even in the adult.

Inherited risk plus prenatal insult caused malignant dysfunction in mesenteric arteries in adolescent SHR offspring.

Prenatal hypoxia can induce cardiovascular diseases in the offspring. This study determined whether and how prenatal hypoxia may cause malignant hypertension and impaired vascular functions in spontaneous hypertension rat (SHR) offspring at adolescent stage. Pregnant SHR were placed in a hypoxic chamber (11% O2) or normal environment (21% O2) from gestational day 6 until birth. Body weight and blood pressure (BP) of SHR offspring were measured every week from 5 weeks old. Mesenteric arteries were tested. Gestational hypoxia resulted in growth restriction during 6–12 weeks and a significant elevation in systolic pressure in adolescent offspring at 12 weeks old. Notably, endothelial vasodilatation of mesenteric arteries was impaired in SHR adolescent offspring exposed to prenatal hypoxia, vascular responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were reduced, as well as plasma nitric oxide levels and expression of endothelial nitric oxide synthase (eNOS) in vessels were decreased. Moreover, mesenteric arteries in SHR offspring following prenatal hypoxia showed enhanced constriction responses to phenylephrine (PE), associated with up-regulated activities of L-type calcium channel (Ca2+-dependent), RhoA/Rock pathway signaling (Ca2+-sensitization), and intracellular Ca2+ flow. Pressurized myograph demonstrated altered mechanical properties with aggravated stiffness in vessels, while histological analysis revealed vascular structural disorganization in prenatal hypoxia offspring. The results demonstrated that blood pressure and vascular function in young SHR offspring were affected by prenatal hypoxia, providing new information on development of hypertension in adolescent offspring with inherited hypertensive backgrounds.

Impact of active lifestyle on heart rate variability and oxidative stress markers in offspring of hypertensives

Familial history of hypertension is associated with autonomic dysfunction and increase in blood pressure (BP). On the other hand, an active lifestyle has been found to improve a number of health outcomes and reduce all‐cause mortality. The aim of the present study was to investigate the effects of an active lifestyle on hemodynamics, heart rate variability (HRV) and oxidative stress markers in offspring of hypertensive parents. One hundred twenty‐seven subjects were assigned into four groups: sedentary offspring of normotensives (S‐ON) or hypertensives (S‐OH); and physically active offspring of normotensives (A‐ON) or hypertensives (A‐OH). The level of physical activity was determined using the International Physical Activity Questionnaire. Heart rate (HR), systolic (SBP) and diastolic BP (DBP) were measured at rest. The assessment of cardiac autonomic modulation was performed by HRV analysis. Oxidant stress was assessed by Hydrogen peroxide concentration, Superoxide anion, Lipid Peroxide levels and Protein Carbonyls measurements in plasma. Diastolic BP and heart rate were reduced in the physically active groups when compared to S‐OH group. A‐ON and A‐OH groups presented increased values of RR total variance when compared to the sedentary ones (A‐ON: 4912±538 vs. S‐ON: 2354±159; A‐OH: 3112±236 vs. S‐OH: 2232±241ms2). Cardiac sympato‐vagal balance (LF/HF), systemic hydrogen peroxide and superoxide anion were markedly increased in S‐OH group when compared to all other studied groups. Systemically, superoxide anion and hydrogen peroxide were increased in S‐OH group when compared to S‐ON group. However, both physically active groups (A‐ON and A‐OH) presented reduced levels of superoxide anion (A‐ON: 41.0±4.1 and A‐OH: 48.3±3.4 vs. S‐OH: 56.7±3.9 nmol/mg of protein) and hydrogen peroxide (A‐ON: 8.95±0.9 and A‐OH: 9.6±1.8 vs. S‐OH: 16.68±2.7 μM) when compared to S‐OH group. Additionally, correlations were observed between LF/HF with diastolic BP (r=0.30, p&lt;0.05) and hydrogen peroxide (r=0.41, p&lt;0.05). Thus, our findings confirm the presence of early autonomic dysfunction in offspring of hypertensive parents, which was associated with a systemic increase in reactive oxygen species and blood pressure. However, our most important finding lies in the attenuation of such disorders in offspring of physically active hypertensives, thus emphasizing the importance of a physically active lifestyle in the prevention of early disorders that may be associated with development of hypertension.Support or Funding InformationFinancial support: UNINOVE, CNPq, CAPES, FAPESP.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

In-utero cold stress causes elevation of blood pressure via impaired vascular dopamine D1 receptor in offspring

ABSTRACTObjective:Environmental cold stress is an important factor that leads to hypertension. The role and the mechanisms of in-utero cold stress in hypertension in adult offspring remain unknown.Methods: The pregnant rats were housed in cold (4°C) rooms from 14 to 21 days of gestation for prenatal cold exposure. The blood pressure and vascular response offspring of control and cold exposure were measured. And the receptor expression, phosphorylation and internalization were checked by immunoblotting or immunoprecipitation.Results: In the present study, we report that prenatal cold stress elevated the blood pressure via decreasing D1 receptor-associated vasodilation, which is ascribed to decreased D1 receptor expression and function. Moreover, the artery G protein-coupled receptor kinase 4 (GRK4) expression has been found to be higher in the prenatal cold stress treated offspring than the controls, which could cause the increased phosphorylation and internalization of D1 receptor in mesenteric artery from prenatal cold stress treated offspring, and led to receptor desensitization and vascular dysfunction.Conclusion: The results illustrate a new paradigm for the developmental origins of hypertension and imply that GRK4 and dopamine D1 receptor may be crucial determinants for the maternal hypertension.

Determinants and impact of masked hypertension in offspring of patients with diabetes: relation with coronary flow and cardiac function

Objective: We aimed to evaluate the prevalence, determinants and clinical impact of masked hypertension in offspring of patients with diabetes. Masked hypertension was defined according to guidelines as daytime ambulatory blood pressure monitoring “ABPM” ≥135/85 mmHg and clinic BP <140/90 mmHg.Methods: 100 nondiabetic offspring of patients with diabetes and 60 offspring of healthy people were enrolled; 24-h ABPM was applied to evaluate mean 24-h systolic/diastolic blood pressure “BP”, daytime, nighttime and night dipping readings. Left ventricular parameters and coronary flow reserve of the left anterior descending artery (induced by adenosine 0.14 mg/kg/min) was calculated in all offspring.Results: 29% of offspring of patients with diabetes had masked hypertension compared to only 3.3% offspring in healthy people (p < 0.001). Compared with those without masked hypertension, offspring with masked hypertension had a significantly reduced coronary flow reserve (p < 0.001), significantly higher E/e' (p < 0.01), [a surrogate marker of left ventricular filling pressure], more microalbuminuria (p < 0.01), and higher values of high-sensitive C-reactive protein “CRP” (p < 0.001). Multivariate regression analysis showed that, fasting blood glucose, and high-sensitive CRP, were independently associated with masked hypertension, whilst daytime systolic BP and non-dipping systolic BP were the strongest predictors for masked hypertension. Logistic regression analysis revealed that masked hypertension was independently associated with reduced coronary flow reserve (p < 0.0001) and diastolic dysfunction (p < 0.001).Conclusion: Masked hypertension is prevalent in offspring of patients with diabetes and significantly associated with reduced coronary flow reserve and left ventricular diastolic dysfunction. These findings suggest that offspring of patients with diabetes constitute a high risk group and deserve close follow up, mainly with the use of ABPM.