Abstract P172: Impairment Of Estrogen Protective Effect Contributes To Maternal Gestational Hypertension-induced Sensitization Of Hypertensive Response To Post-weaning High Fat Diet In Female Adult Offspring

Obesity/high fat diet (HFD) is a risk factor for cardiovascular diseases including hypertension. Recent evidence indicates that maternal gestational hypertension (MGHT) induces hypertensive response sensitization (HTRS) elicited by post-weaning HFD in both male and female offspring. However, the increase in blood pressure (BP) in female offspring is less than that in male offspring. In this study, we investigated if estrogen plays a protective role in MGHT-induced HTRS to post-weaning HFD in female offspring, and if estrogen effects are associated with regulation of brain reactivity to pressor agents and altered autonomic function. In post-weaning HFD fed intact female offspring, MGHT induced HFD-elicited HTRS (MAP, offspring of NT dams, 107.9±0.9 to 115.2±0.7 mmHg; offspring of MGHT dams, 107.3±0.8 to 120.7±1.4 mmHg, p<0.05) and enhanced pressor responses to centrally administered angiotensin (ANG) II (Δ13.7±1.1 mmHg, p<0.05 vs NFD offspring) and tumor necrosis factor α (TNF-α) (Δ13.1±0.7 mmHg, p<0.05 vs NFD offspring). Ovariectomy (OVX) significantly enhanced the HFD-induced increase in BP (115.2±0.7 to 127.1±2.2 mmHg, p<0.05) and the pressor response to central ANG II (Δ11.2±0.9 to Δ18.7±2.3 mmHg, p<0.05) or TNF-α (Δ10.0±1.0 to Δ16.5±1.6 mmHg, p<0.05) in HFD offspring of normotensive (NT) dams. However, MGHT-induced HTRS (MAP, 122.5±1.9 mmHg) and pressor responses to ANG II (Δ16.3±1.0 mmHg) or TNF-α (Δ14.9±1.0 mmHg) in HFD-fed intact offspring of MGHT dams were not potentiated further after OVX when compared to HFD-fed OVX offspring of NT dams. The resting BP and elicited pressor responses remained higher than that of NFD fed offspring of both NT and MGHT dams. Moreover, OVX induced an increase in central nervous system sympathetic drive, and HFD feeding potentiated this effect. The results indicate that estrogen normally plays a protective role in antagonizing HFD prohypertensive effects in offspring of NT dams. MGHT compromises this normal protective action of estrogen to induce HTRS elicited by HFD, which is through augmenting brain reactivity and centrally driven sympathetic activity.

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Loss of the Protective Effect of Estrogen Contributes to Maternal Gestational Hypertension‐Induced Hypertensive Response Sensitization Elicited by Postweaning High‐Fat Diet in Female Offspring

Journal of the American Heart Association ◽

10.1161/jaha.121.023685 ◽

2022 ◽

Author(s):

Baojian Xue ◽

Yang Yu ◽

Terry G. Beltz ◽

Fang Guo ◽

Shun‐Guang Wei ◽

...

Keyword(s):

Blood Pressure ◽

High Fat Diet ◽

Gestational Hypertension ◽

Female Offspring ◽

Protective Role ◽

High Fat ◽

Intact Female ◽

Pressor Responses ◽

Factor Α ◽

Necrosis Factor

Background A recent study conducted in male offspring demonstrated that maternal gestational hypertension (MHT) induces hypertensive response sensitization (HTRS) elicited by postweaning high‐fat diet (HFD). In this study, we investigated the sensitizing effect of MHT on postweaning HFD‐induced hypertensive response in female rat offspring and assessed the protective role of estrogen in HTRS. Methods and Results The results showed that MHT also induced a sensitized HFD‐elicited hypertensive response in intact female offspring. However, compared with male offspring, this MHT‐induced HTRS was sex specific in that intact female offspring exhibited an attenuated increase in blood pressure. Ovariectomy significantly enhanced the HFD‐induced increase in blood pressure and the pressor response to centrally administered angiotensin II or tumor necrosis factor‐α in offspring of normotensive dams, which was accompanied by elevated centrally driven sympathetic activity, upregulated mRNA expression of prohypertensive components, and downregulated expression of antihypertensive components in the hypothalamic paraventricular nucleus. However, when compared with HFD‐fed ovariectomized offspring of normotensive dams, the MHT‐induced HTRS and pressor responses to centrally administered angiotensin II or tumor necrosis factor‐α in HFD‐fed intact offspring of MHT dams were not potentiated by ovariectomy, but the blood pressure and elicited pressor responses as well as central sympathetic tone remained higher. Conclusions The results indicate that in adult female offspring MHT induced HTRS elicited by HFD. Estrogen normally plays a protective role in antagonizing HFD prohypertensive effects, and MHT compromises this normal protective action of estrogen by augmenting brain reactivity and centrally driven sympathetic activity.

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Abstract P194: Voluntary Exercise Eliminates Maternal Gestational Hypertension-induced Hypertensive Response Sensitization (htrs) In Post-weaning High Fat Diet Fed Male Adult Offspring

Hypertension ◽

10.1161/hyp.78.suppl_1.p194 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Baojian Xue ◽

Yang Yu ◽

terry beltz ◽

Fang Guo ◽

Shun-Guang Wei ◽

...

Keyword(s):

High Fat Diet ◽

Gestational Hypertension ◽

Sympathetic Tone ◽

Male Offspring ◽

Voluntary Exercise ◽

Ang Ii ◽

High Fat ◽

Male Adult ◽

Pressor Responses ◽

Resting Blood Pressure

Exercise has profound effects on cardiovascular function and metabolism in both physiological and pathophysiological states. Our previous studies demonstrated that maternal gestational hypertension (MGHT) induces hypertensive response sensitization (HTRS) elicited by post-weaning high fat diet (HFD) in male offspring. The present study tested whether voluntary exercise would protect against MGHT-induced HTRS in HFD fed male offspring. Male offspring from both normotensive (NT) and MGHT dams were given access to either “blocked” (sedentary offspring) or functional running (exercised offspring) wheels for 10 weeks during normal fat diet (NFD) or HFD feeding. HFD feeding significantly increased resting blood pressure (BP) in sedentary offspring of both NT (112.3±0.7 to 119.9±1.2 mmHg, p<0.05) and MGHT (112.5±0.9 to 129.6±1.0 mmHg, p<0.05) dams, but the elevated BP induced by HFD was greater in sedentary offspring of MGHT dams (129.6±1.0 vs. 119.9±1.2 mmHg, p<0.05). The sedentary offspring of MGHT dams also displayed greater sympathetic tone and enhanced pressor responses to centrally administrated angiotensin (ANG) II or leptin. The running distance was comparable in four groups of exercise offspring (9.183±1.183, 9.192±1.677, 7.233±1.080, 8.482±1.455 kilometers/day, p>0.05). Voluntary exercise did not alter BP in NFD fed offspring and HFD fed offspring of NT dams, but it attenuated BP in HFD fed offspring of MGHT dams (129.6±1.0 to 121.1±0.8 mmHg, p<0.05) and body weight and heart rate in all offspring. Moreover, voluntary exercise significantly reduced sympathetic tone (Hexamethonium, ip, MAP Δ-50.6±1.0 to Δ-29.7±2.7 mmHg, p<0.05) and pressor responses to central ANG II and leptin in HFD fed offspring of both NT (ANG II: Δ16.0±0.9 to Δ7.5±1.1 mmHg; leptin: Δ11.8±0.6 to Δ5.4±0.9 mmHg, p<0.05) and MGHT (ANG II: Δ24.3±2.1 to Δ7.6±1.8 mmHg; leptin: Δ16.8±0.9 to Δ5.2±1.0 mmHg, p<0.05) dams and eliminated the differences in these responses between NFD fed offspring and HFD fed offspring. These results indicate that exercise training plays a beneficial role in preventing MGHT-induced HTRS and that this effect is associated with reduced brain reactivity to pressor stimuli and centrally driven sympathetic activity.

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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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00200.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. R351-R359 ◽

Cited By ~ 2

Author(s):

Xue-Fang Wang ◽

Jian-Dong Li ◽

Yan-Li Huo ◽

Yu-Ping Zhang ◽

Zhi-Qin Fang ◽

...

Keyword(s):

High Fat Diet ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Adult Offspring ◽

Ang Ii ◽

Converting Enzyme ◽

High Fat ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

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.

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Hypersensitivity to acute ANG II in female growth-restricted offspring is exacerbated by ovariectomy

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00219.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. R1199-R1205 ◽

Cited By ~ 23

Author(s):

Norma B. Ojeda ◽

Suttira Intapad ◽

Thomas P. Royals ◽

Joshua T. Black ◽

John Henry Dasinger ◽

...

Keyword(s):

Pressor Response ◽

Renin Angiotensin System ◽

Female Offspring ◽

Ang Ii ◽

Angiotensin System ◽

Intact Control ◽

Enhanced Sensitivity ◽

Renal Hemodynamic ◽

Pressor Responses ◽

Before And After

Female growth-restricted offspring are normotensive in adulthood. However, ovariectomy induces a marked increase in mean arterial pressure (MAP) that is abolished by renin angiotensin system (RAS) blockade, suggesting RAS involvement in the etiology of hypertension induced by ovariectomy in adult female growth-restricted offspring. Blockade of the RAS also abolishes hypertension in adult male growth-restricted offspring. Moreover, sensitivity to acute ANG II is enhanced in male growth-restricted offspring. Thus, we hypothesized that an enhanced sensitivity to acute ANG II may contribute to hypertension induced by ovariectomy in female growth-restricted offspring. Female offspring were subjected to ovariectomy (OVX) or sham ovariectomy (intact) at 10 wk of age. Cardio-renal hemodynamic parameters were determined before and after an acute infusion of ANG II (100 ng·kg−1·min−1 for 30 min) at 16 wk of age in female offspring pretreated with enalapril (40 mg·kg−1·day−1 for 7 days). Acute ANG II induced a significant increase in MAP in intact growth-restricted offspring (155 ± 2 mmHg, P < 0.05) relative to intact control (145 ± 4 mmHg). Ovariectomy augmented the pressor response to ANG II in growth-restricted offspring (163 ± 2 mmHg, P < 0.05), with no effect in control (142 ± 2 mmHg). Acute pressor responses to phenylephrine did not differ in growth-restricted offspring relative to control, intact, or ovariectomized. Furthermore, renal hemodynamic responses to acute ANG II were significantly enhanced only in ovariectomized female growth-restricted offspring. Thus, these data suggest that enhanced responsiveness to acute ANG II is programmed by intrauterine growth restriction and that sensitivity to acute ANG II is modulated by ovarian hormones in female growth-restricted offspring.

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Maternal high-fat diet acts on the brain to induce baroreflex dysfunction and sensitization of angiotensin II-induced hypertension in adult offspring

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00698.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. H1061-H1069 ◽

Cited By ~ 9

Author(s):

Yu-Ping Zhang ◽

Yan-Li Huo ◽

Zhi-Qin Fang ◽

Xue-Fang Wang ◽

Jian-Dong Li ◽

...

Keyword(s):

Nadph Oxidase ◽

Proinflammatory Cytokines ◽

High Fat Diet ◽

Control Diet ◽

Renin Angiotensin System ◽

Adult Offspring ◽

Ang Ii ◽

High Fat ◽

Pressor Responses ◽

The Brain

Accumulating evidence indicates that maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular disease in adult offspring. The present study tested the hypothesis that maternal HFD modulates the brain renin-angiotensin system (RAS), oxidative stress, and proinflammatory cytokines that alter angiotensin II (ANG II) and TNF-α actions and sensitize the ANG II-elicited hypertensive response in adult offspring. All offspring were cross fostered by dams on the same or opposite diet to yield the following four groups: offspring from normal-fat control diet-fed dams suckled by control diet-fed dams (OCC group) or by HFD-fed dams (OCH group) and offspring from HFD-fed dams fed a HFD suckled by control diet-fed dams (OHC group) or by HFD-fed dams (OHH group). RT-PCR analyses of the lamina terminalis and paraventricular nucleus indicated upregulation of mRNA expression of several RAS components, NADPH oxidase, and proinflammatory cytokines in 10-wk-old male offspring of dams fed a HFD during either pregnancy, lactation, or both (OHC, OCH, and OHH groups). These offspring also showed decreased cardiac baroreflex sensitivity and increased pressor responses to intracerebroventricular microinjection of either ANG II or TNF-α. Furthermore, chronic systemic infusion of ANG II resulted in enhanced upregulation of mRNA expression of RAS components, NADPH oxidase, and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus and an augmented hypertensive response in the OHC, OCH, and OHH groups compared with the OCC group. The results suggest that maternal HFD blunts cardiac baroreflex function and enhances pressor responses to ANG II or proinflammatory cytokines through upregulation of the brain RAS, oxidative stress, and inflammation. NEW & NOTEWORTHY The results of our study indicate that a maternal high-fat diet during either pregnancy or lactation is sufficient for perinatal programming of sensitization for hypertension, which is associated with hyperreactivity of central cardiovascular nuclei that, in all likelihood, involves elevated expression of the renin-angiotensin system, NADPH oxidase, and proinflammatory cytokines. The present study demonstrates, for the first time, the central mechanism underlying maternal high-fat diet sensitization of the hypertensive response in adult offspring.

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Effects of Maternal Flaxseed Supplementation on Female Offspring of Diabetic Rats in Serum Concentration of Glucose, Insulin, and Thyroid Hormones

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000259 ◽

2019 ◽

Vol 89 (1-2) ◽

pp. 45-54

Author(s):

Akemi Suzuki ◽

André Manoel Correia-Santos ◽

Gabriela Câmara Vicente ◽

Luiz Guillermo Coca Velarde ◽

Gilson Teles Boaventura

Keyword(s):

Thyroid Hormones ◽

High Fat Diet ◽

Female Offspring ◽

Flaxseed Oil ◽

Diabetic Rats ◽

High Fat ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Flaxseed Flour ◽

Maternal Consumption

Abstract. Objective: This study aimed to evaluate the effect of maternal consumption of flaxseed flour and oil on serum concentrations of glucose, insulin, and thyroid hormones of the adult female offspring of diabetic rats. Methods: Wistar rats were induced to diabetes by a high-fat diet (60%) and streptozotocin (35 mg/kg). Rats were mated and once pregnancy was confirmed, were divided into the following groups: Control Group (CG): casein-based diet; High-fat Group (HG): high-fat diet (49%); High-fat Flaxseed Group (HFG): high-fat diet supplemented with 25% flaxseed flour; High-fat Flaxseed Oil group (HOG): high-fat diet, where soya oil was replaced with flaxseed oil. After weaning, female pups (n = 6) from each group were separated, received a commercial rat diet and were sacrificed after 180 days. Serum insulin concentrations were determined by ELISA, the levels of triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH) were determined by chemiluminescence. Results: There was a significant reduction in body weight at weaning in HG (−31%), HFG (−33%) and HOG (44%) compared to CG (p = 0.002), which became similar by the end of 180 days. Blood glucose levels were reduced in HFG (−10%, p = 0.044) when compared to CG, and there was no significant difference between groups in relation to insulin, T3, T4, and TSH after 180 days. Conclusions: Maternal severe hyperglycemia during pregnancy and lactation resulted in a microsomal offspring. Maternal consumption of flaxseed reduces blood glucose levels in adult offspring without significant effects on insulin levels and thyroid hormones.

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