Norma B. Ojeda

Sex differences in the fetal programming of hypertension.

BACKGROUND Numerous clinical and experimental studies support the hypothesis that the intrauterine environment is an important determinant of cardiovascular disease and hypertension. OBJECTIVE This review examined the mechanisms linking an adverse fetal environment and increased risk for chronic disease in adulthood with an emphasis on gender differences and the role of sex hormones in mediating sexual dimorphism in response to a suboptimal fetal environment. METHODS This review focuses on current findings from the PubMed database regarding animal models of fetal programming of hypertension, sex differences in phenotypic outcomes, and potential mechanisms in offspring of mothers exposed to an adverse insult during gestation. For the years 1988 to 2007, the database was searched using the following terms: fetal programming, intrauterine growth restriction, low birth weight, sex differences, estradiol, testosterone, high blood pressure, and hypertension. RESULTS The mechanisms involved in the fetal programming of adult disease are multifactorial and include alterations in the regulatory systems affecting the long-tterm control of arterial pressure. Sex differences have been observed in animal models of fetal programming, and recent studies suggest that sex hormones may modulate activity of regulatory systems, leading to a lower incidence of hypertension and vascular dysfunction in females compared with males. CONCLUSIONS Animal models of fetal programming provide critical support for the inverse relationship between birth weight and blood pressure. Experimental models demonstrate that sex differences are observed in the pathophysiologic response to an adverse fetal environment. A role for sex hormone involvement is strongly suggested,with modulation of the renin-angiotensin system as a possible mechanism.

Estrogen Protects Against Increased Blood Pressure in Postpubertal Female Growth Restricted Offspring

Placental insufficiency in the rat results in intrauterine growth restriction and development of hypertension in prepubertal male and female growth-restricted offspring. However, after puberty, only male growth-restricted offspring remain hypertensive, whereas female growth-restricted offspring stabilize their blood pressure to levels comparable to adult female controls. Because female rats reach their maximum levels of estrogen at puberty, we hypothesize that estrogen may be a factor involved in the stabilization of blood pressure in adult female growth-restricted offspring. At 10 weeks of age, female control and growth-restricted offspring underwent ovariectomy or sham surgery and insertion of a telemetry probe. Mean arterial pressure was similar at 16 weeks of age between control (123±4 mm Hg) and growth-restricted offspring (122±2 mm Hg); however, ovariectomy led to a significant increase in blood pressure in growth-restricted offspring (140±2 mm Hg; P<0.05 versus intact counterpart) with no significant effect in controls (124±1 mm Hg). Estrogen replacement by subcutaneous minipellet initiated at 14 weeks of age in a subset of ovariectomized control and growth-restricted offspring reversed the effect of ovariectomy on blood pressure in growth-restricted offspring at 16 weeks of age (111±3 mm Hg; P<0.05 versus ovariectomized counterpart); renin angiotensin system blockade also abolished ovariectomy-induced hypertension in female growth-restricted offspring (106±2 mm Hg; P<0.05 versus ovariectomized counterpart). Therefore, sex differences are observed in this model of fetal programmed hypertension, and results from this study suggest that estrogen contributes to normalization of blood pressure in adult female growth-restricted offspring.

Intrauterine growth restriction: fetal programming of hypertension and kidney disease.

The etiology of hypertension historically includes 2 components: genetics and lifestyle. However, recent epidemiologic studies report an inverse relationship between birth weight and hypertension suggesting that a suboptimal fetal environment may also contribute to increased disease in later life. Experimental studies support this observation and indicate that cardiovascular/kidney disease originates in response to fetal adaptations to adverse conditions during prenatal life.

Developmental Programming of Hypertension: Insight From Animal Models of Nutritional Manipulation

Low birth weight (LBW), defined as a birth weight of ≤2.5 kg at term, is a major health issue within the United States today. The risk for LBW is greater within the black population than the white, with a greater percentage of LBW occurring within the southern United States relative to other parts of the country.1 Infants born small for gestational age not only have a greater risk for survival at birth2,3 but, based on numerous epidemiological studies, face long-term consequences, such as increased risk for development of hypertension, cardiovascular disease, diabetes, and other health problems.4–6 Barker7 first proposed that an adverse environmental stimulus experienced during a critical period of fetal development leads to slow fetal growth and permanent structural and physiological changes in the fetus predisposing it to increased risk for the development of hypertension and cardiovascular disease. Investigators using animal models to induce an adverse fetal environment and mimic the human condition of slow fetal growth are providing convincing evidence to support the concept of developmental programming of adult disease.8–17 Although there is compelling epidemiological and experimental data that suggest that cardiovascular diseases such as hypertension may be programmed in utero, the underlying pathophysiological mechanisms remain unclear. Investigators use unique animal models of nutritional manipulation to induce slow fetal growth to examine the mechanisms linking birth weight and chronic adult disease, such as hypertension. In this review, we discuss alterations in potential mechanistic pathways that evolve in response to fetal insult and lead to the developmental programming of hypertension, highlighting insight provided by animal models of nutritional manipulation. Nutritional restriction is one of the most common experimental methods of fetal insult used for investigation into the mechanisms of programmed hypertension and was one of the first to demonstrate that exposure to an adverse …

Renal Denervation Abolishes the Age-Dependent Increase in Blood Pressure in Female Intrauterine Growth-Restricted Rats at 12 Months of Age

Perinatal insults program sex differences in blood pressure, with males more susceptible than females. Aging may augment developmental programming of chronic disease, but the mechanisms involved are not clear. We previously reported that female growth-restricted offspring are normotensive after puberty. Therefore, we tested the hypothesis that age increases susceptibility to hypertension in female growth-restricted offspring. Blood pressure remained similar at 6 months of age; however, blood pressure was significantly elevated in female growth-restricted offspring relative to control by 12 months of age (137±3 vs 117±4 mm Hg; P<0.01, respectively). Body weight did not differ at 6 or 12 months of age; however, total fat mass and visceral fat were significantly increased at 12 months in female growth-restricted offspring (P<0.05 vs control). Glomerular filtration rate remained normal, yet renal vascular resistance was increased at 12 months of age in female growth-restricted offspring (P<0.05 vs control). Plasma leptin, which can increase sympathetic nerve activity, did not differ at 6 months but was increased at 12 months of age in female growth-restricted offspring (P<0.05 vs control). Because of the age-dependent increase in leptin, we hypothesized that the renal nerves may contribute to the age-dependent increase in blood pressure. Bilateral renal denervation abolished the elevated blood pressure in female growth-restricted offspring normalizing it relative to denervated female control offspring. Thus, these data indicate that age induces an increase in visceral fat and circulating leptin associated with a significant increase in blood pressure in female growth-restricted offspring, with the renal nerves serving as an underlying mechanism.

EARLY RENAL DENERVATION PREVENTS DEVELOPMENT OF HYPERTENSION IN GROWTH-RESTRICTED OFFSPRING

1 Low birth weight is associated with an increased risk for the development of hypertension. Our laboratory uses a model of reduced uterine perfusion in the pregnant rat that results in intrauterine growth‐restricted (IUGR) offspring that develop hypertension at a prepubertal age. Although hypertension develops in both prepubertal male and female IUGR offspring, only male IUGR offspring remain hypertensive after puberty. We reported previously that bilateral renal denervation abolishes hypertension in adult male IUGR offspring, indicating an important role for the renal nerves in the maintenance of established IUGR‐induced hypertension. We also reported that angiotensin‐converting enzyme inhibition abolishes hypertension in adult male IUGR offspring. However, activation of the renin–angiotensin system does not occur in male IUGR offspring until after puberty, or after the development of established IUGR‐induced hypertension. Therefore, the mechanisms involved in the development of IUGR‐induced hypertension may differ from those involved in the maintenance of established IUGR‐induced hypertension. Thus, the purpose of the present study was to determine whether the renal nerves play a causative role in the early development of IUGR‐induced hypertension in prepubertal IUGR offspring. 2 Intrauterine growth‐restricted and control offspring were subjected to either bilateral renal denervation or sham denervation, respectively, at 4 weeks of age. Mean arterial pressure (MAP) was determined at 6 weeks of age in conscious, chronically instrumented animals. Adequacy of renal denervation was verified by renal noradrenaline content. 3 Whereas renal denervation had no effect on MAP in control offspring (103 ± 2 vs 102 ± 3 mmHg for sham vs denervated, respectively), it reduced blood pressure in growth‐restricted offspring (114 ± 3 vs 104 ± 1 mmHg for sham vs denervated, respectively; P < 0.01). Renal noradrenaline content was significantly reduced in denervated animals relative to sham operated rats. 4 Thus, the data indicate a role for the renal nerves in the aetiology of IUGR‐induced hypertension and suggest that the renal nerves may participate in the early development of hypertension in IUGR offspring in addition to established hypertension observed in adult male IUGR offspring.

Enhanced sensitivity to acute angiotensin II is testosterone dependent in adult male growth-restricted offspring.

Placental insufficiency results in intrauterine growth restriction (IUGR) and hypertension in adult male growth-restricted rats. Although renal ANG II and plasma renin activity do not differ between growth-restricted and control rats, blockade of the renin-angiotensin system (RAS) abolishes hypertension in growth-restricted rats, suggesting that the RAS contributes to IUGR-induced hypertension. Moreover, castration abolishes hypertension in growth-restricted rats, indicating an important role for testosterone. Therefore, we hypothesized that enhanced responsiveness to ANG II contributes to hypertension in this model of IUGR and that androgens may play a pivotal role in this enhanced response. Physiological parameters were determined at 16 wk of age in male rats pretreated with enalapril (40 mg.kg(-1).day(-1)) for 1 wk. Baseline blood pressures were similar between growth-restricted (112 +/- 3 mmHg) and control (110 +/- 2 mmHg) rats; however, an enhanced pressor response to acute ANG II (100 ng.kg(-1).min(-1) for 30 min) was observed in growth-restricted (160 +/- 2 mmHg) vs. control (136 +/- 2 mmHg; P < 0.05) rats. Castration abolished the enhanced pressor response to acute ANG II in growth-restricted (130 +/- 2 mmHg) rats with no significant effect on blood pressure in controls (130 +/- 2 mmHg). Blood pressure was increased to a similar extent above baseline in response to acute phenylephrine (100 microg/min) in control (184 +/- 5 mmHg) and growth-restricted (184 +/- 8 mmHg) rats, suggesting the enhanced pressor response in growth-restricted rats is ANG II specific. Thus, these results suggest that growth-restricted rats exhibit an enhanced responsiveness to ANG II that is testosterone dependent and indicate that the RAS may serve as an underlying mechanism in mediating hypertension programmed in response to IUGR.

Oxidative Stress Contributes to Sex Differences in Blood Pressure in Adult Growth-Restricted Offspring

Numerous experimental studies suggest that oxidative stress contributes to the pathophysiology of hypertension and, importantly, that oxidative stress plays a more definitive role in mediating hypertension in males than in females. Intrauterine growth restriction induced by reduced uterine perfusion initiated at day 14 of gestation in the rat programs hypertension in adult male growth-restricted offspring; yet, female growth-restricted offspring are normotensive. The mechanisms mediating sex differences in blood pressure in adult growth-restricted offspring are not clear. Thus, this study tested the hypothesis that sex-specific differences in renal oxidative stress contribute to the regulation of blood pressure in adult growth-restricted offspring. A significant increase in blood pressure measured by telemetry in male growth-restricted offspring (P<0.05) was associated with a marked increase in renal markers of oxidative stress (P<0.05). Chronic treatment with the antioxidant Tempol had no effect on blood pressure in male control offspring, but it normalized blood pressure (P<0.05) and renal markers of oxidative stress (P<0.05) in male growth-restricted offspring relative to male control offspring. Renal markers of oxidative stress were not elevated in female growth-restricted offspring; however, renal activity of the antioxidant catalase was significantly elevated relative to female control offspring (P<0.05). Chronic treatment with Tempol did not significantly alter oxidative stress or blood pressure measured by telemetry in female offspring. Thus, these data suggest that sex differences in renal oxidative stress and antioxidant activity are present in adult growth-restricted offspring and that oxidative stress may play a more important role in modulating blood pressure in male but not female growth-restricted offspring.

Sex Differences in the Developmental Origins of Cardiovascular Disease

The Developmental Origins of Health and Disease (DOHaD) proposes that adverse events during early life program an increased risk for cardiovascular disease. Experimental models provide proof of concept but also indicate that insults during early life program sex differences in adult blood pressure and cardiovascular risk. This review will highlight the potential mechanisms that contribute to the etiology of sex differences in the developmental programming of cardiovascular disease.

Sex differences in the developmental programming of hypertension

Experimental models of developmental programming provide proof of concept and support Barkers original findings that link birthweight and blood pressure. Many experimental models of developmental insult demonstrate a sex difference with male offspring exhibiting a higher blood pressure in young adulthood relative to their age‐matched female counterparts. It is well recognized that men exhibit a higher blood pressure relative to age‐matched women prior to menopause. Yet, whether this sex difference is noted in individuals born with low birthweight is not clear. Sex differences in the developmental programming of blood pressure may originate from innate sex‐specific differences in expression of the renin angiotensin system that occur in response to adverse influences during early life. Sex differences in the developmental programming of blood pressure may also involve the influence of the hormonal milieu on regulatory systems key to the long‐term control of blood pressure such as the renin angiotensin system in adulthood. In addition, the sex difference in blood pressure in offspring exposed to a developmental insult may involve innate sex differences in oxidative status or the endothelin system or may be influenced by age‐dependent changes in the developmental programming of cardiovascular risk factors such as adiposity. Therefore, this review will highlight findings from different experimental models to provide the current state of knowledge related to the mechanisms that contribute to the aetiology of sex differences in the developmental programming of blood pressure and hypertension.