Blood Pressure In Adult Offspring Research Articles

Renal Oxidative Stress May Explain Sex Differences in Blood Pressure in Adult Offspring Exposed to an Impoverished Environment

Background: Nearly 40 million people experience poverty in the United States. Poverty is linked to adverse childhood experiences (ACEs) which affects about 64% of adults in the U.S. Previous studies indicate that those who experience ACEs are at a higher risk of developing hypertension (HTN) and cardiovascular diseases (CVDs) later in life, with a greater severity and earlier onset in males. The mechanisms behind the ACEs-attributed development of sex differences in HTN later in life is unknown. One plausible mechanism for this sex difference is increased oxidative stress. One rodent model to mimic poverty as an ACE is the limited bed and nesting (LBN) model. This model simulates an impoverished and low resource environment, as observed in poverty, in which the nesting material during weaning is reduced. We hypothesize that male offspring exposed to LBN will have elevated blood pressure and oxidative stress, while females will have no change in blood pressure and reduced oxidative stress. Methods: Pregnant Sprague Dawley rats gave birth naturally and weaned their offspring for 3 weeks. During the weaning period, on Days 2-9, the dams and their respective pups were divided into 2 groups: LBN and control (CON). After LBN treatment, all rats received normal bedding. After weaning, offspring were divided by sex and experimental status: LBN male (n=5), LBN female (n=5), CON male (n=6), and CON female (n=6). At 16-17 weeks, mean arterial pressure (MAP) was measured via carotid catheterization and the kidneys, brain, heart, and plasma were collected to measure antioxidant capacity via colorimetric biochemical assays. Results: LBN males had a significant increase (18 mmHg) in MAP compared to CON males (128.17±3.93 vs 110.72± 3.93 mmHg, P>0.001), while female LBN and CON rodents displayed no differences. In males, there were no changes in antioxidant capacity in the brain, heart, and plasma. However, there was a significant 2-fold decrease in renal antioxidant capacity (233±14.0 vs 442±12.3 mM Trolox/mg protein, p>0.0001). In females, there were no changes in the kidneys, heart, and brain antioxidant capacity. Conversely, LBN females showed a trending increase in plasma antioxidant capacity compared to CON (3.33±0.16 vs 2.53±0.35 mM Trolox/mg protein, p=0.053). Conclusion: Only males exposed to an impoverished environment during weaning have elevated blood pressure, while females do not. This difference in blood pressure may be explained by decreases in renal antioxidant capacity in males only. On the other hand, females may be protected from elevated blood pressure because they experience a slight increase in systemic antioxidant capacity. Future studies will examine the role of antioxidants in blood pressure regulation in the kidneys. This study is clinically relevant because ACEs affect a large percentage of the American population with about 17% of adults experiencing 4 or more ACEs, with minorities at a greater risk. Understanding the mechanisms on how ACEs contribute to HTN may alleviate some of the racial and ethnic disparities, along with the financial burden on the healthcare system to care for people with HTN and CVDs. Perhaps, organ and sex-specific antioxidant therapies may be used to alter, prevent, or reduce the development of HTN in adults that were exposed to ACEs, such as poverty during nursing and early childhood. This research was supported by start-up funds and the American Heart Association Early Career Development Award [AHA 18CDA34110264 (Cunningham)]. 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.

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.

Perinatal taurine exerts a hypotensive effect in male spontaneously hypertensive rats and down‐regulates endothelial oxide nitric synthase in the aortic arch

Essential hypertension is considered to be a result of the interaction between genetic and environmental factors, including perinatal factors. Different advantageous perinatal factors proved to have beneficial long-lasting effects against an abnormal genetic background. Taurine is a ubiquitous sulphur-containing amino acid present in foods such as seafood. The antihypertensive effects of taurine have been reported in experimental studies and in human hypertension. We aimed to investigate the effects of perinatal treatment with taurine in spontaneously hypertensive rats (SHR), a known model of genetic hypertension. Female SHR were administered with taurine (3g/L) during gestation and lactation (SHR-TAU). Untreated SHR and Wistar-Kyoto rats (WKY) were used as controls. Long-lasting effects in offspring were investigated. Addition of taurine to the mother's drinking water reduced blood pressure in adult offspring. No differences were observed in cardiac hypertrophy. Findings on morphometric evaluations suggest that perinatal treatment with taurine would be partially effective in improving structural alterations of the aorta. Modifications in gene expression of Bcl-2 family members and upregulation of endothelial nitric oxide synthase in the aorta of 22-week-old male offspring were found. No differences were observed on relative telomere length in different cardiovascular tissues between SHR and SHR-TAU. Altogether results suggest that taurine programming, albeit sex specific, is associated with gene expression changes which ultimately may lead to improvement of aortic remodelling and enhanced endothelial function because of augmented nitric oxide (NO) production.

Resveratrol prevents combined prenatal NG-nitro-L-arginine-methyl ester (L-NAME) treatment plus postnatal high-fat diet induced programmed hypertension in adult rat offspring: interplay between nutrient-sensing signals, oxidative stress and gut microbiota

Oxidative stress, nutrient-sensing signals, high-fat (HF) intake and dysbiosis of gut microbiota are involved in the development of hypertension, a disorder that can originate in early life. We examined whether postnatal HF diet can aggravate maternal NG-nitro-L-arginine-methyl ester (L-NAME) treatment-induced programmed hypertension and whether resveratrol therapy can prevent it. Pregnant Sprague–Dawley rats received L-NAME administration at 60 mg/kg/day subcutaneously during pregnancy alone, or with additional resveratrol (R) 50 mg/L in drinking water during the pregnancy and lactation. The offspring were onto either regular chow or HF diet (D12331) from weaning to 16 weeks of age. Male offspring rats were assigned to five groups (N=8/group): control, L-NAME, HF, L-NAME+HF and L-NAME+HF + R at weaning at 3 weeks of age. Rats were sacrificed at 16 weeks of age. We observed that postnatal HF diet exacerbates maternal L-NAME treatment-induced programmed hypertension in male adult offspring, which resveratrol attenuated. Combined L-LAME and HF diet-induced hypertension is related to increased oxidative stress, inhibiting AMP-activated protein kinase (AMPK)/ peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) pathway and altered gut microbiota compositions. L-NAME+HF caused an increase of the Firmicutes to Bacteroidetes ratio, which resveratrol therapy prevented. Additionally, the abundances of phylum Verrucomicrobia and genus Akkermansia were amplified by resveratrol therapy. Conclusively, our data highlighted the interactions between maternal NO deficiency, HF diet, AMPK/PGC-1α pathway and gut microbiota in which the blood pressure of adult offspring can be modified by resveratrol. Resveratrol might be a useful reprogramming strategy to prevent L-NAME and HF diet-induced hypertension of developmental origin.

In utero exposure to ultrafine particles promotes placental stress-induced programming of renin-angiotensin system-related elements in the offspring results in altered blood pressure in adult mice

BackgroundExposure to particulate matter (PM) is associated with an adverse intrauterine environment, which can promote adult cardiovascular disease (CVD) risk. Ultrafine particles (UFP) (small size and large surface area/mass ratio) are systemically distributed, induce inflammation and oxidative stress, and have been associated with vascular endothelial dysfunction and arterial vasoconstriction, increasing hypertension risk. Placental stress and alterations in methylation of promoter regions of renin-angiotensin system (RAS)-related elements could be involved in UFP exposure-related programming of hypertension. We investigated whether in utero UFP exposure promotes placental stress by inflammation and oxidative stress, alterations in hydroxysteroid dehydrogenase 11b-type 2 (HSD11B2) and programming of RAS-related elements, and result in altered blood pressure in adult offspring. UFP were collected from ambient air using an aerosol concentrator and physicochemically characterized. Pregnant C57BL/6J pun/pun female mice were exposed to collected UFP (400 μg/kg accumulated dose) by intratracheal instillation and compared to control (nonexposed) and sterile H2O (vehicle) exposed mice. Embryo reabsorption and placental stress by measurement of the uterus, placental and fetal weights, dam serum and fetal cortisol, placental HSD11B2 DNA methylation and protein levels, were evaluated. Polycyclic aromatic hydrocarbon (PAH) biotransformation (CYP1A1 and NQO1 (NAD(P)H dehydrogenase (quinone)1)) enzymes, inflammation and oxidative stress in placentas and fetuses were measured. Postnatal day (PND) 50 in male offspring blood pressure was measured. Methylation and protein expression of (RAS)-related elements, angiotensin II receptor type 1 (AT1R) and angiotensin I-converting enzyme (ACE) in fetuses and lungs of PND 50 male offspring were also assessed.ResultsIn utero UFP exposure induced placental stress as indicated by an increase in embryo reabsorption, decreases in the uterus, placental, and fetal weights, and HSD11B2 hypermethylation and protein downregulation. In utero UFP exposure induced increases in the PAH-biotransforming enzymes, intrauterine oxidative damage and inflammation and stimulated programming and activation of AT1R and ACE, which resulted in increased blood pressure in the PND 50 male offspring.ConclusionsIn utero UFP exposure promotes placental stress through inflammation and oxidative stress, and programs RAS-related elements that result in altered blood pressure in the offspring. Exposure to UFP during fetal development could influence susceptibility to CVD in adulthood.

Perinatal and long-term effects of maternal uterine artery adenoviral VEGF-A165 gene therapy in the growth-restricted guinea pig fetus.

Uterine artery application of adenoviral vascular endothelial growth factor A165 (Ad.VEGF-A165) gene therapy increases uterine blood flow and fetal growth in experimental animals with fetal growth restriction (FGR). Whether Ad.VEGF-A165 reduces lifelong cardiovascular disease risk imposed by FGR remains unknown. Here, pregnant guinea pigs fed 70% normal food intake to induce FGR received Ad.VEGF-A165 (1×1010 viral particles, n = 15) or vehicle ( n = 10), delivered to the external surface of the uterine arteries, in midpregnancy. Ad libitum-fed controls received vehicle only ( n = 14). Litter size, gestation length, and perinatal mortality were similar in control, untreated FGR, and FGR+Ad.VEGF-A165 animals. When compared with controls, birth weight was lower in male but higher in female pups following maternal nutrient restriction, whereas both male and female FGR+Ad.VEGF-A165 pups were heavier than untreated FGR pups ( P < 0.05, ANOVA). Postnatal weight gain was 10-20% greater in female FGR+Ad.VEGF-A165 than in untreated FGR pups, depending on age, although neither group differed from controls. Maternal nutrient restriction reduced heart weight in adult female offspring irrespective of Ad.VEGF-A165 treatment but did not alter ventricular wall thickness. In males, postnatal weight gain and heart morphology were not affected by maternal treatment. Neither systolic, diastolic, mean arterial pressure, adrenal weight, nor basal or challenged plasma cortisol were affected by maternal undernutrition or Ad.VEGF-A165 in either sex. Therefore, increased fetal growth conferred by maternal uterine artery Ad.VEGF-A165 is sustained postnatally in FGR female guinea pigs. In this study, we did not find evidence for an effect of maternal nutrient restriction or Ad.VEGF-A165 therapy on adult offspring blood pressure.

Effect of renal denervation on urine angiotensinogen excretion in prenatally programmed rats

Prenatal programming results in an increase in blood pressure in adult offspring. We have shown that compared to control adult offspring whose mothers were fed a 20% protein diet, programmed adults whose mothers were fed a 6% protein diet during the last half of pregnancy have an increase in renal sympathetic nerve activity and urinary angiotensinogen/creatinine levels. We hypothesized that the increase in urinary angiotensinogen was mediated by renal sympathetic nerve activity in programmed rats. In this study performed in 3 month old rats, renal denervation resulted in normalization of blood pressure in the 6% programmed group (150 ± 3 Hg in 6% sham vs. 121 ± 4 Hg in 6% denervated, P < 0.001), and a reduction in blood pressure in the 20% group (126 ± 2 Hg 20% sham vs. 113 ± 4 Hg 20% denervated (P < 0.05). We confirm that the intrarenal renin–angiotensin system assessed by urinary angiotensinogen/creatinine is upregulated in offspring of rats fed a 6% protein diet rats compared to 20% controls. To determine if sympathetic nerve activity was mediating the increase in urinary angiotensinogen in programmed rats, we compared denervated to sham‐operated control and programmed rats. Renal denervation had no effect on urinary angiotensinogen/creatinine ratio in the 20% group and no effect on the increased urinary angiotensinogen/creatinine ratio found in programmed rats. This study demonstrates that the increase in urinary angiotensinogen in programmed rats is not mediated by renal sympathetic nerve activity.

Maternal Renovascular Hypertensive Rats Treatment With Hydrogen Sulfide Increased the Methylation of AT1b Gene in Offspring.

A large number of studies have shown hypertension of offspring in adulthood is related to parental health during pregnancy. Hydrogen sulfide (H2S) could relax placental vasculature and improve intrauterine growth restriction. In the present study, we want to observe the effect of H2S on the fetal programming of renovascular hypertension, a rat model of secondary hypertension. Renovascular hypertension was induced by 2-kidney-1-clip, their adult pups were used to evaluate basal blood pressure. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured noninvasively by tail-cuff plethysmography in conscious offspring; HE staining was used to observe morphology of kidney; the protein expression of angiotensin II receptor 1 (AT1R) tested by western blot; methylation of angiotensin II receptor 1b (AT1b) gene used pBLUE-T-cloning to check. The SBP and DBP in the offspring of renovascular hypertensive dams were higher than those in control group. Moreover, interstitial inflammatory infiltration was significant in the kidney and the protein expression of AT1R was also increased in the offspring of renovascular hypertensive dams. Conversely, methylation of AT1b promoter (U01033 277-1611) decreased in the first 3 CG sites. Either prenatal or postnatal treatment with H2S could increase the methylation of AT1b and downregulate AT1R expression then improve the blood pressure. These results suggested that parental secondary hypertension-induced kidney damage that elevated basal blood pressure in adult offspring. Prenatal or postnatal administration with H2S induced improved effect accompanied by an increased methylation of AT1b gene then downregulated protein of AT1R in offspring.

Prenatal Exposure to LPS Alters The Intrarenal RAS in Offspring, Which Is Ameliorated by Adipose Tissue-Derived Mesenchymal Stem Cells.

Prenatal lipopolysaccharide (LPS) exposure causes hypertension in rat offspring through an unknown mechanism. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) in hypertension induced by prenatal LPS exposure and also explored whether adipose tissue-derived mesenchymal stem cells (ADSCs) can ameliorate the effects of prenatal LPS exposure in rat offspring. Sixty-four pregnant rats were randomly divided into 4 groups (n = 16 in each), namely, a control group and an LPS group, which were intraperitoneally injected with vehicle and 0.79 mg/kg LPS, respectively, on the 8th, 10th, and 12th days of gestation; an ADSCs group, which was intravenously injected with 1.8 × 107 ADSCs on the 8th, 10th, and 12th days of gestation; and an LPS + ADSCs group, which received a combination of the treatments administered to the LPS and ADSCs groups. Prenatal LPS exposure increased blood pressure, Ang II expression, Ang II-positive, monocyte and lymphocyte, apoptotic cells in the kidney, and induced renal histological changes in offspring; however, the LPS and control groups did not differ significantly with respect to plasma renin activity levels, Ang II levels, or renal function. ADSCs treatment attenuated the blood pressure and also ameliorated the other effects of LPS-treated adult offspring. Prenatal exposure to LPS activates the intrarenal RAS but not the circulating RAS and thus induces increases in blood pressure in adult offspring; however, ADSCs treatment attenuates the blood pressure increases resulting from LPS exposure and also ameliorates the other phenotypic changes induced by LPS treatment by inhibiting intrarenal RAS activation.

Alterations in perivascular innervation function in mesenteric arteries from offspring of diabetic rats.

We have reported that exposure to a diabetic intrauterine environment during pregnancy increases blood pressure in adult offspring, but the mechanisms involved are not completely understood. This study was designed to analyse a possible role of perivascular sympathetic and nitrergic innervation in the superior mesenteric artery (SMA) in this effect. Diabetes was induced in pregnant Wistar rats by a single injection of streptozotocin. Endothelium-denuded vascular rings from the offspring of control (O-CR) and diabetic rats (O-DR) were used. Vasomotor responses to electrical field stimulation (EFS), NA and the NO donor DEA-NO were studied. The expressions of neuronal NOS (nNOS) and phospho-nNOS (P-nNOS) and release of NA, ATP and NO were determined. Sympathetic and nitrergic nerve densities were analysed by immunofluorescence. Blood pressure was higher in O-DR animals. EFS-induced vasoconstriction was greater in O-DR animals. This response was decreased by phentolamine more in O-DR animals than their controls. L-NAME increased EFS-induced vasoconstriction more strongly in O-DR than in O-CR segments. Vasomotor responses to NA or DEA-NO were not modified. NA, ATP and NO release was increased in segments from O-DR. nNOS expression was not modified, whereas P-nNOS expression was increased in O-DR. Sympathetic and nitrergic nerve densities were similar in both experimental groups. The activity of sympathetic and nitrergic innervation is increased in SMA from O-DR animals. The net effect is an increase in EFS-induced contractions in these animals. These effects may contribute to the increased blood pressure observed in the offspring of diabetic rats.

Postnatal Dietary Omega-3 Fatty Acid Supplementation Rescues Glucocorticoid-Programmed Adiposity, Hypertension, and Hyperlipidemia in Male Rat Offspring Raised on a High-Fat Diet

Fetal glucocorticoid excess programs several adverse outcomes in adult offspring, many of which can be prevented by postnatal, dietary omega-3 (n-3) fatty acids. Here we tested 2 separate hypotheses: 1) a postnatal high-fat diet exacerbates the glucocorticoid-programmed phenotype; and 2) postnatal, dietary n-3 fatty acids rescue programmed outcomes, even in the presence of a high-fat diet challenge. Pregnant Wistar rat dams were either untreated or administered dexamethasone acetate (Dex; 0.5 μg/mL drinking water) from day 13 of pregnancy. Offspring were cross-fostered to untreated mothers and males were weaned onto a standard (Std), high-fat, low n-3 (HF), or high-fat, high n-3 (HFHn-3) diet. Prenatal Dex reduced birth weight (26%) and delayed puberty onset by 1.2 days, irrespective of postnatal diet. Prenatal Dex programmed increased blood pressure in adult offspring, an effect worsened by the postnatal HF diet. Supplementation with high n-3 fatty acids, however, prevented both the Dex and HF-induced increases in blood pressure. Prenatal Dex also programmed increased adiposity, plasma cholesterol, and plasma triglyceride levels at 6 months of age, particularly in those offspring raised on the HF diet. But again, each of these adverse outcomes was rescued by supplementation of the HF diet with n-3 fatty acids. In conclusion, the capacity of n-3 fatty acids to overcome adverse programming outcomes remains evident, even in the presence of a HF diet challenge.

Exploring the relationship between maternal iron status and offspring&amp;rsquo;s blood pressure and adiposity:&amp;nbsp;a Mendelian randomization study

BackgroundIron deficiency is the most common micronutrient deficiency worldwide. Experimental animal studies suggest that mothers deficient in iron during pregnancy are more likely to have offspring who become obese with high blood pressure. C282Y mutation carriers are more likely to have higher iron stores.MethodsWe undertook an instrumental variable (IV) analysis, using maternal C282Y as an indicator for the mother’s iron status, to examine its association with offspring blood pressure (BP), waist circumference (WC), and body mass index (BMI), and compared the results to that of ordinary least squares (OLS) regression. Offspring of a sub-cohort of mothers from the UK Women’s Cohort Study (UKWCS) were recruited in 2009–2010 (n = 348, mean age = 41 years). Their blood pressure, height, and weight were measured at their local general medical practice, and they were asked to self-measure their waist circumference. About half were offspring of C282Y carriers. Maternal ferritin was used as a biomarker of maternal iron status.ResultsMaternal C282Y was strongly associated with maternal ferritin (mean difference per allele = 84 g/L, 95% confidence interval: 31–137, P = 0.002). Using IV analyses, maternal ferritin was not linked to offspring’s BP, BMI, or WC. The first stage F-statistic for the strength of the instrument was 10 (Kleibergen–Paap rk LM P = 0.009). Maternal ferritin was linked to offspring diastolic BP, WC, and BMI in univariable, but not in multivariable OLS analysis. There was no difference between the OLS and the IV models coefficients for any of the outcomes considered.ConclusionWe found no association between maternal iron status and adult offspring’s BP and adiposity using both multivariable OLS and IV modeling. To our knowledge, this is the first study examining this relationship. Further exploration in larger studies that have genetic variation assessed in both mother and offspring should be considered.

640: In utero inflammation alters the cardiovascular response of adult offspring

The effect of the uterine environment on adult vascular function has been well documented. Our previous studies have shown that exposure to significant inflammation at day 16 gestation in mice alters the in vitro carotid artery vascular reactivity in the adult offspring. Our objective in this study was to test the hypothesis that exposure to inflammation in late gestation alters the adult offspring's blood pressure both during normal activity and in endotoxin-induced shock.

Prenatal betamethasone exposure alters renal function in immature sheep: sex differences in effects

Synthetic glucocorticoids are commonly given to pregnant women when premature delivery threatens. Antenatal administration of clinically relevant doses of betamethasone to pregnant sheep causes sex-specific compromises of renal function and increases in blood pressure in adult offspring. However, it is unclear whether such effects are present in immature lambs. Therefore, the aims of the present study were to determine whether antenatal betamethasone at 80-81 days of gestation increases blood pressure and adversely impacts renal function in adolescent ewes and rams. Prenatal steroid exposure increased blood pressure significantly in the young male (84 +/- 2 vs. 74 +/- 3 mmHg) and female sheep (88 +/- 5 vs. 79 +/- 4), but it did not alter basal glomerular filtration rate, renal blood flow (RBF), or sodium excretion in either sex. However, antenatal betamethasone exposure blocked increases in RBF (P = 0.001), and enhanced excretion of an acute Na load (P < 0.05) in response to systemic infusions of angiotensin (ANG)-(1-7) at 10 pmol.kg(-1).min(-1) in males. In females, the natriuretic response to combined ANG-(1-7), and Na load was significantly altered by prenatal betamethasone exposure. These findings indicate that blood pressure is increased in immature animals in response to antenatal steroid exposure and that sex-specific effects on renal function also exist. These changes may reflect greater risk for further loss of renal function with age.

Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon

The "programming hypothesis" proposes that an adverse perinatal milieu leads to adaptation that translates into cardiovascular disease in adulthood. The balance between nitric oxide (NO) and reactive oxygen species (ROS) is disturbed in cardiovascular diseases, including hypertension. Conceivably, this balance is also disturbed in pregnancy, altering the fetal environment; however, effects of perinatal manipulation of NO and ROS on adult blood pressure (BP) are unknown. In spontaneously hypertensive rats (SHR), NO availability is decreased and ROS are increased compared with normotensive Wistar-Kyoto rats, and, despite the genetic predisposition, the perinatal environment can modulate adult BP. Our hypothesis is that a disturbed NO-ROS balance in the SHR dam persistently affects BP in her offspring. Dietary supplements, which support NO formation and scavenge ROS, administered during pregnancy and lactation resulted in persistently lower BP for up to 48 wk in SHR offspring. The NO donor molsidomine and the superoxide dismutase mimic tempol-induced comparable effects. Specific inhibition of inducible nitric oxide synthase (NOS) reduces BP in adult SHR, suggesting that inducible NOS is predominantly a source of ROS in SHR. Indeed, inducible NOS inhibition in SHR dams persistently reduced BP in adult offspring. Persistent reductions in BP were accompanied by prevention of proteinuria in aged SHR. We propose that in SHR the known increase in ANG II type 1 receptor density during development leads to superoxide production, which enhances inducible NOS activity. The relative shortage of substrate and cofactors leads to uncoupling of inducible NOS, resulting in superoxide production, activating transcription factors that subsequently again increase inducible NOS expression. This vicious circle probably is perpetuated into adult life.

Betamethasone in the last week of pregnancy causes fetal growth retardation but not adult hypertension in rats.

We tested the hypotheses that (1) maternal betamethasone (betaM) treatment over the range of clinical doses for prevention of prematurity-related pathologies from day 15 to 21 of rat gestation would produce growth retardation, and (2) the lowest betaM dose to produce growth retardation would result in hypertension in adult offspring. In experiment 1, pregnant Sprague-Dawley rats were administered betaM (0, 50, 100, 200, 400, or 600 microg/kg per day, subcutaneously) on days 15-21 of pregnancy and necropsied on day 21.5, with fetal lung and placental weights recorded. In experiment 2, two more groups of rats (0 or 100 microg/kg per day, subcutaneously) were allowed to deliver, and offspring were instrumented at 100 +/- 4 days of postnatal life with indwelling left carotid arterial catheters. After 48 hours of recovery, blood pressure was recorded continuously for 24 hours. In experiment 1, all newborn rats treated with betaM, and their placentas, except those receiving 50 microg/kg per day, were growth retarded in comparison with controls (P <.05). All treated lungs were smaller than those of controls (P <.05). In experiment 2, no differences were found in the mean arterial blood pressure of adult offspring given the lowest effective dose of betaM (100 microg/kg per day) compared with controls (114.2 +/- 5.3 mmHg versus 114.6 +/- 3.4 mmHg, respectively). These data suggest that glucocorticoids given in the last week of rat pregnancy in the lowest human clinical dose do not cause hypertension and somatic growth retardation. However, the presence of lung growth restriction at this dose argues for more studies on the efficacy of even lower concentrations for their ability to improve lung and other organ and tissue function while avoiding unwanted side effects.

Mechanisms Underlying the Programming of Small Artery Dysfunction: Review of the Model Using Low Protein Diet in Pregnancy in the Rat

Human and animal studies have shown that unbalanced maternal nutrition is associated with the development of cardiovascular and metabolic disease in adulthood. In the Southampton maternal low protein model (SMLP), protein deprivation (50%) throughout pregnancy in rats leads to elevated blood pressure in adult offspring. Impaired peripheral arterial function may contribute to the cardiovascular dysfunction observed in these offspring. This review discusses the impact of such a dietary insult on the vascular function of resistance arteries from pregnant rats (pF 0), their offspring (F 1), the pregnant offspring (pF 1) and the second generation (F 2). At each stage, disturbances in endothelium-dependent relaxation were observed, implicating changes in endothelial nitric oxide (NO)-guanylate cyclase (GC) signalling pathway in the vascular adaptations to pregnancy and the programmed effects on offspring.

Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring.

Increasing evidence from human epidemiological studies suggests that poor growth before birth is associated with postnatal growth retardation and the development of cardiovascular disease in adulthood. We have shown previously that nutritional deprivation in the pregnant rat leads to intrauterine growth retardation (IUGR), postnatal growth failure, changes in the endocrine parameters of the somatotrophic axis, and to increased blood pressure in later life. In the present study, we investigated whether administration of insulin-like growth factor-I (IGF-I) or bovine growth hormone (GH) during pregnancy could prevent IUGR and/or alter long-term outcome. Dams from day 1 of pregnancy throughout gestation received a diet of ad libitum available food or a restricted dietary intake of 30% of ad libitum fed dams. From day 10 of gestation, dams were treated for 10 days with three times daily subcutaneous injections of saline (100 microl), IGF-I (2 micrograms/g body weight) or GH (2 micrograms/g body weight). Maternal weight gain was significantly increased (P<0.001) in ad libitum fed dams treated with GH, (98.9+/-4.73 g) compared with the IGF-I (80.5+/-2.17 g) and saline-treated (70.7+/-2.65 g) groups. There was a small increase in maternal weight gain (P<0.06) in 30% ad libitum fed dams following GH (16.3+/-2.47 g) and IGF-I (15.8+/-1.97 g) treatment compared with saline (9.2+/-1.96 g). Whole spleen, kidney and carcass weights were significantly (P<0.05) increased in ad libitum fed and 30% ad libitum fed dams with GH treatment. Circulating IGF-I was significantly increased (P<0.001) in ad libitum fed dams with both IGF-I (369.6+/-32.33 ng/ml) and GH (457.9+/-33.32 ng/ml) compared with saline treatment (211.7+/-14.02 ng/ml), and with GH (223.4+/-23.72 ng/ml) compared with saline treatment (112.0+/-7.33 ng/ml) in 30% ad libitum fed dams. Circulating GH binding protein (GHBP) levels were significantly reduced (P<0.05) in GH-treated (299.1+/-51.54 ng/ml) compared with saline-treated (503.9+/-62.43 ng/ml) ad libitum fed dams, but were not altered in 30% ad libitum fed dams. There was no significant effect of either IGF-I or GH treatment on fetal weight, placental weight, fetal organ weights or circulating IGF-I levels in both ad libitum fed and 30% ad libitum fed fetuses. Offspring of 30% ad libitum fed dams remained significantly growth retarded postnatally and showed elevated blood pressure in later life. The increased maternal weight gain following IGF-I or GH administration, without an effect on fetal and placental weights, suggests a modification in the mode of maternal nutrient repartitioning during mid to late pregnancy at the expense of the fetus.

High NaCl intake of rat dams alters maternal behavior and elevates blood pressure of adult offspring

The present study investigated whether differences in maternal NaCl intake altered 1) maternal-pup behavior and 2) the development of dietary obesity and blood pressure level of adult Sprague-Dawley rats maintained on a palatable high-fat/milk (HF/M) diet. Thirteen dams fed high (3%) NaCl and 12 dams fed basal (0.12%) NaCl were observed on postnatal days 2-21 for differences in the number of times spent 1) nursing, 2) in contact with or licking, sniffing, and carrying pups, and 3) in nest building. The offspring were continued on their respective NaCl diets to 30 days postpartum, and then both NaCl groups were fed an intermediate (1%) NaCl diet thereafter. Beginning at 60 days of age, the offspring from each maternal NaCl condition were fed either Agway R-M-H 1000 pelleted food or a HF/M diet for 14 wk. Dams fed 3% NaCl spent significantly more time licking their pups than did dams fed 0.12% NaCl. The adult offspring of dams fed 3% NaCl had a significantly higher level of systolic blood pressure and consumed more calories of sweetened condensed milk on the HF/M diet than did rats raised on 0.12% NaCl. Dietary-induced obesity did not magnify the increase in systolic blood pressure from high maternal NaCl intake. The present results raise the possibility that increased maternal licking may contribute to the increased blood pressure and solution intake that follows from high maternal NaCl intake.