Daniela Grigore

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 …

Role of fetal programming in the development of hypertension

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.

Functional Complementation of the Yeast P-type H+-ATPase, PMA1, by the Pneumocystis carinii P-type H+-ATPase, PCA1

ABSTRACT. The opportunistic fungus Pneumocystis is the etiologic agent of an interstitial plasma cell pneumonia that primarily afflicts immunocompromised individuals. Like other fungi Pneumocystis maintains a H+ plasma membrane gradient to drive nutrient uptake and regulates intracellular pH by ATP‐dependent proton efflux. Previously, we identified a Pneumocystis gene, PCA1, whose predicted protein product was homologous to fungal proton pumps. In this study, we show by functional complementation in a Saccharomyces strain whose endogenous PMA1 proton pump activity is repressed that the Pneumocystis PCA1 encodes a H+‐ATPase. The properties of PCA1 characterized in this system closely resemble those of yeast PMA1. Yeast expressing PCA1 grow at low pH and are able to acidify the external media. Maximal enzyme activity (Vmax) and efficiency of substrate utilization (Km) in plasma membranes were nearly identical for PCA1 and PMA1. PCA1 contains an inhibitory COOH‐terminal domain; removal of the final 40 amino acids significantly increased Vmax and growth at pH 6.5. PCA1 activity was inhibited by proton pump inhibitors omeprazole and lansoprazole, but was unaffected by H+/K+‐ATPase inhibitor SCH28080. Thus, H+ homeostasis in Pneumocystis is likely regulated as in other fungi. This work also establishes a system for screening PCA1 inhibitors to identify new anti‐Pneumocystis agents.