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.

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 ± 34 vs. 189 ± 12 ng/dl, P < 0.05) was associated with a significant increase in mean arterial pressure (MAP) measured by telemetry in IUGR offspring (147 ± 1 vs. 125 ± 1 mmHg, P < 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 ± 2 mmHg, P < 0.05 vs. intact IUGR) but had no effect in control (125 ± 2 mmHg). A significant decrease in MAP in intact IUGR (111 ± 3 mmHg, P < 0.05 vs. untreated intact IUGR) and castrated IUGR (110 ± 4 mmHg, P < 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 (Δ36 ± 1 mmHg, P < 0.05) compared with CTX IUGR (Δ15 ± 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.

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·kg⁻¹·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.

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.

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.