Abstract-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 (123Ϯ4 mm Hg) and growth-restricted offspring (122Ϯ2 mm Hg); however, ovariectomy led to a significant increase in blood pressure in growth-restricted offspring (140Ϯ2 mm Hg; PϽ0.05 versus intact counterpart) with no significant effect in controls (124Ϯ1 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 (111Ϯ3 mm Hg; PϽ0.05 versus ovariectomized counterpart); renin angiotensin system blockade also abolished ovariectomy-induced hypertension in female growth-restricted offspring (106Ϯ2 mm Hg; PϽ0.05 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. Key Words: fetal programming Ⅲ intrauterine growth restriction Ⅲ ovariectomy Ⅲ estrogen Ⅲ renin angiotensin system H ypertension shows a clear age-related sex dimorphism. Nearly 1 in 3 adult Americans have hypertension. A higher percentage of men than women have hypertension until age 45 years, the percentage is similar from ages 45 to 54 years, and it becomes higher for women after that. 1 Thus, the risk of hypertension increases in women after the onset of menopause and continues to rise with age. 1-4 As a result, after menopause, a greater percentage of women have hypertension than age-matched men. 1,5,6 Epidemiological evidence suggests a regulatory role for estrogens in maintaining vascular function and structure. 7-9 Loss of ovarian function results in estrogen deficiency and increased risk for development of cardiovascular diseases, such as hypertension in postmenopausal women and women with ovarian surgical ablation. [7][8][9][10] In animal models of hypertension in which female rats are normotensive relative to their hypertensive male counterparts, ovariectomy induces hypertension. 11-14 Therefore, it seems that, while the ovaries are functional, women have a lower risk of cardiovascular disease than men, an observation supported by experimental studies.Alte...

Our laboratory uses a model of intrauterine growth restriction (IUGR) induced by placental insufficiency in the rat to examine the developmental origins of adult disease. In this model only male IUGR offspring remain hypertensive in adulthood, revealing sex-specific differences. The purpose of this study was to determine whether testosterone with participation of the renin-angiotensin system (RAS) contributes to hypertension in adult male IUGR offspring. At 16 wk of age a significant increase in testosterone (346 Ϯ 34 vs. 189 Ϯ 12 ng/dl, P Ͻ 0.05) was associated with a significant increase in mean arterial pressure (MAP) measured by telemetry in IUGR offspring (147 Ϯ 1 vs. 125 Ϯ 1 mmHg, P Ͻ 0.05, IUGR vs. control, respectively). Gonadectomy (CTX) at 10 wk of age significantly reduced MAP by 16 wk of age in IUGR offspring (124 Ϯ 2 mmHg, P Ͻ 0.05 vs. intact IUGR) but had no effect in control (125 Ϯ 2 mmHg). A significant decrease in MAP in intact IUGR (111 Ϯ 3 mmHg, P Ͻ 0.05 vs. untreated intact IUGR) and castrated IUGR (110 Ϯ 4 mmHg, P Ͻ 0.05 vs. untreated CTX IUGR) after treatment with enalapril for 2 wk suggests a role for RAS involvement. However, the decrease in blood pressure in response to enalapril was greater in intact IUGR (⌬36 Ϯ 1 mmHg, P Ͻ 0.05) compared with CTX IUGR (⌬15 Ϯ 2 mmHg), indicating an enhanced response to RAS blockade in the presence of testosterone. Thus these results suggest that testosterone plays a role in modulating hypertension in adult male IUGR offspring with participation of the RAS.

Background-Numerous clinical and experimental studies support the hypothesis that the intrauterine environment is an important determinant of cardiovascular disease and hypertension.

Reduced uterine perfusion initiated in late gestation in the rat results in intrauterine growth restriction (IUGR) and development of hypertension by 4 wk of age. We hypothesize that the renin angiotensin system (RAS), a regulatory system important in the long-term control of blood pressure, may be programmed by placental insufficiency and may contribute to the etiology of IUGR hypertension. We previously reported that RAS blockade abolished hypertension in adult IUGR offspring; however, the mechanisms responsible for the early phase of hypertension are unresolved. Therefore, the purpose of this study was to examine RAS involvement in early programmed hypertension and to determine whether temporal changes in RAS expression are observed in IUGR offspring. Renal renin and angiotensinogen mRNA expression were significantly decreased at birth (80 and 60%, respectively); plasma and renal RAS did not differ in conjunction with hypertension (mean increase of 14 mmHg) in young IUGR offspring; however, hypertension (mean increase of 22 mmHg) in adult IUGR offspring was associated with marked increases in renal angiotensin-converting enzyme (ACE) activity (122%) and renal renin and angiotensinogen mRNA (7-fold and 7.4-fold, respectively), but no change in renal ANG II or angiotensin type 1 receptor. ACE inhibition (enalapril, 10 mg x kg(-1) x day(-1), administered from 2 to 4 wk of age) abolished hypertension in IUGR at 4 wk of age (decrease of 15 mmHg, respectively) with no significant depressor effect in control offspring. Therefore, temporal alterations in renal RAS are observed in IUGR offspring and may play a key role in the etiology of IUGR hypertension.

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.

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Epidemiological studies have suggested that size at birth contributes to increased cardiovascular disease (CVD) risk in later life. Findings from experimental studies are providing insight into the mechanisms linking impaired fetal growth and the increased risk of CVD and hypertension in adulthood. This article summarizes potential mechanisms involved in the fetal programming of hypertension and CVD, including alterations in the organs and regulatory systems critical to long-term control of sodium and volume homeostasis.

Numerous epidemiological studies report a link between intrauterine growth restriction (IUGR) and hypertension. Our laboratory utilizes a unique model of IUGR by inducing placental insufficiency in the rat during late gestation. The response to placental ischemia in the pregnant rat is characterized by hypertension associated with endothelial dysfunction accompanied by increased inflammatory cytokines, mimicking the maternal syndrome of preeclampsia. Offspring born of the hypertensive dams exhibit IUGR and develop an increase in blood pressure (BP) by 4 weeks of age. We hypothesized that elevated inflammatory cytokines may be a contributing factor to the increased BP in IUGR offspring. We examined the circulating cytokine profile, via cytokine protein array analysis, in plasma of IUGR and control offspring at 4 weeks of age. Approximately 60% of all cytokines examined were significantly up‐regulated in IUGR offspring compared to control offspring. The increase in Interferon gamma, Interleukin‐1, and macrophage inflammatory protein are characteristic of endothelial dysfunction which could contribute to the development of the hypertension in the IUGR offspring. In conclusion, the circulating cytokine profile which is significantly altered in IUGR offspring compared to control offspring may be indicative of chronic inflammation associated with IUGR in response to placental insufficiency.