1. Recent studies in animals have linked fetal exposure to excess maternal glucocorticoids with the later occurrence of cardiovascular disorders, particularly hypertension. 2. To test the hypothesis that prenatal treatment could impact on adult blood pressure two groups of pregnant ewes were transported from the farm to the Institute at either 22-29 days of pregnancy (pretreatment group 1) or 59-66 days of pregnancy (pretreatment group 2), subjected to 48 h treatment with dexamethasone (0.28 mg day-1 kg-1 for 2 days) and then returned to the farm. The control group remained at the farm for the entire pregnancy. Lambs were then studied at approximately 4, 10 and 19 months after birth. 3. The basal mean arterial pressure in pretreatment group 1 (80 +/- 1 mmHg at 124 days; 83 +/- 1 mmHg at 309 days and 89 +/- 1 mmHg at 558 days; n = 6) was significantly different (P < 0.05 in all groups) from that in the control group of lambs (74 +/- 2 mmHg at 110 days; 76 +/- 1 mmHg at 323 days and 81 +/- 1 mmHg at 568 days; n = 7). However, prenatal glucocorticoid exposure did not alter vascular sensitivity to noradrenaline, angiotensin II and adrenocorticotropic hormone in these sheep at any of the ages studied, nor did it affect basal or adrenocorticotropic hormone-induced concentrations of cortisol or basal plasma renin concentrations in the lambs at any age. 4. These data support the hypothesis that excess glucocorticoid exposure in early pregnancy, during a critical developmental stage or 'window', programmes higher blood pressure that persists in later life.

Renal morphology in adult control and prenatally dexamethasone-treated animals Representative photomicrographs of the renal cortex from two animals from the control group (CON; A and B) and four animals prenatally treated with dexamethasone (DEX; C-F); Tissues shown in A and E were stained with haematoxylin and eosin and those in B, C, D and F were stained with Masson trichrome. In three out of four DEX animals (C, D and F) the proximal tubules (large arrows) were markedly dilated and enlarged. There was no noticeable collagen accumulation in the glomeruli of any animal, but excess collagen can be seen in the tubular interstitium and the periadventitia of cortical vessels (small arrows). Bar represents 50 mm.

Abstract-Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of the present study were to see whether prenatal dexamethasone administered intravenously to the ewe between 26 to 28 days of gestation (1) resulted in high blood pressure in male and female offspring and whether hypertension in males was modulated by testosterone status, and (2) altered gene expression for angiotensinogen and angiotensin type 1 (AT 1 ) receptors in the brain in late gestation and in the adult. Basal mean arterial pressure (MAP) at 2 years of age was significantly higher in wethers exposed to prenatal dexamethasone (group D; 106Ϯ5 mm Hg, nϭ9) compared with the control group (group S; 91Ϯ3 mm Hg, nϭ8; PϽ0.01). Infusion of testosterone for 3 weeks had no effect on MAP in either treatment group. Key Words: brain Ⅲ glucocorticoids Ⅲ hypertension, experimental Ⅲ sheep E pidemiological evidence suggests that babies born small for gestational age have an increased incidence of adultonset diseases or dysfunction, including syndrome X (hypertension, non-insulin-dependent diabetes mellitus, and hyperlipidemia). [1][2][3] It is hypothesized that a suboptimal intrauterine environment during a critical stage of development permanently alters, or "programs," the development of fetal tissues. This may ensure the short-term survival of the fetus but also may bring adverse consequences in postnatal life.Animal models using maternal undernutrition or restriction of specific dietary components (iron, protein), either throughout pregnancy or during parts of gestation, have confirmed that restriction of fetal growth leads to elevated blood pressure in the progeny of rats. 4 -6 A second type of animal model has examined the long-term/programming effects caused by prenatal glucocorticoid exposure. When adult rats were exposed to large doses of carbenoxolone (an 11␤-hydroxysteroid dehydrogenase [HSD] inhibitor, which blocks placental inactivation of endogenous glucocorticoids) throughout gestation, offspring were of low birth weight and had high blood pressure. 7-9 The synthetic glucocorticoid dexamethasone, which is poorly metabolized by placental 11␤-HSD, given throughout rat pregnancy resulted in offspring with high blood pressure. 10 In the sheep, we 11 have shown that exposure to dexamethasone, for 2 days very early in gestation (at a mean age of 27 days of the 150-day gestation period) results in hypertensive female offspring by 3 to 4 months of age. This hypertension amplifies with age and is associated with an increased cardiac output. 12 By 7 years of age, these animals had developed left ventricular hypertrophy with reduced cardiac functional reserve. 13 In these studies, only female offspring were studied. However, in many models, the programming effects of the prenatal treatment are only seen in male offspring, 14 or they were more pronounced in male offspring compared with female offspring. 4 These studies proposed that programming, at least in some models, may be gender specific....

There is now extensive evidence suggesting that intrauterine perturbations are linked with an increased risk of developing cardiovascular disease. Human epidemiological studies, supported by animal models, have demonstrated an association between low birth weight, a marker of intrauterine growth restriction (IUGR), and adult cardiovascular disease. However, little is known of the early influence of IUGR on the fetal heart and vessels. The aim of this study was to determine the effects of late gestational IUGR on coronary artery function and cardiomyocyte maturation in the fetus. IUGR was induced by placental embolization in fetal sheep from 110 to 130 days of pregnancy (D110-130); term ∼D147; control fetuses received saline. At necropsy (D130), wire and pressure myography was used to test endothelial and smooth muscle function, and passive mechanical wall properties, respectively, in small branches of left descending coronary arteries. Myocardium was dissociated for histological analysis of cardiomyocytes. At D130, IUGR fetuses (2.7 ± 0.1 kg) were 28% lighter than controls (3.7 ± 0.3 kg; P = 0.02). Coronary arteries from IUGR fetuses had enhanced responsiveness to the vasoconstrictors, angiotensin II and the thromboxane analogue U46619, than controls (P < 0.01). Endothelium-dependent and -independent relaxations were not different between groups. Coronary arteries of IUGR fetuses were more compliant (P = 0.02) than those of controls. The incidence of cardiomyocyte binucleation was lower in the left ventricles of IUGR fetuses (P = 0.02), suggestive of retarded cardiomyocyte maturation. We conclude that late gestational IUGR alters the reactivity and mechanical wall properties of coronary arteries and cardiomyocyte maturation in fetal sheep, which could have lifelong implications for cardiovascular function.

Abstract-Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of the present study were to see whether prenatal dexamethasone administered intravenously to the ewe between 26 to 28 days of gestation (1) resulted in high blood pressure in male and female offspring and whether hypertension in males was modulated by testosterone status, and (2) altered gene expression for angiotensinogen and angiotensin type 1 (AT 1 ) receptors in the brain in late gestation and in the adult. Basal mean arterial pressure (MAP) at 2 years of age was significantly higher in wethers exposed to prenatal dexamethasone (group D; 106Ϯ5 mm Hg, nϭ9) compared with the control group (group S; 91Ϯ3 mm Hg, nϭ8; PϽ0.01). Infusion of testosterone for 3 weeks had no effect on MAP in either treatment group. Key Words: brain Ⅲ glucocorticoids Ⅲ hypertension, experimental Ⅲ sheep E pidemiological evidence suggests that babies born small for gestational age have an increased incidence of adultonset diseases or dysfunction, including syndrome X (hypertension, non-insulin-dependent diabetes mellitus, and hyperlipidemia). [1][2][3] It is hypothesized that a suboptimal intrauterine environment during a critical stage of development permanently alters, or "programs," the development of fetal tissues. This may ensure the short-term survival of the fetus but also may bring adverse consequences in postnatal life.Animal models using maternal undernutrition or restriction of specific dietary components (iron, protein), either throughout pregnancy or during parts of gestation, have confirmed that restriction of fetal growth leads to elevated blood pressure in the progeny of rats. 4 -6 A second type of animal model has examined the long-term/programming effects caused by prenatal glucocorticoid exposure. When adult rats were exposed to large doses of carbenoxolone (an 11␤-hydroxysteroid dehydrogenase [HSD] inhibitor, which blocks placental inactivation of endogenous glucocorticoids) throughout gestation, offspring were of low birth weight and had high blood pressure. 7-9 The synthetic glucocorticoid dexamethasone, which is poorly metabolized by placental 11␤-HSD, given throughout rat pregnancy resulted in offspring with high blood pressure. 10 In the sheep, we 11 have shown that exposure to dexamethasone, for 2 days very early in gestation (at a mean age of 27 days of the 150-day gestation period) results in hypertensive female offspring by 3 to 4 months of age. This hypertension amplifies with age and is associated with an increased cardiac output. 12 By 7 years of age, these animals had developed left ventricular hypertrophy with reduced cardiac functional reserve. 13 In these studies, only female offspring were studied. However, in many models, the programming effects of the prenatal treatment are only seen in male offspring, 14 or they were more pronounced in male offspring compared with female offspring. 4 These studies proposed that programming, at least in some models, may be gender specific....

This study demonstrates that chronically, EBP is associated with significant atrial electrical and structural remodelling. These changes may explain the increased propensity to atrial arrhythmias observed with long-standing EBP.

Recent evidence, from both epidemiological and animal experimental studies, suggest that the very first environment, the intrauterine, is extremely important in determining the future health of the individual. Genetic and 'lifestyle' factors impinge on, and can exacerbate, a 'programming' effect of an adverse fetal environment. In this review, we present compelling evidence to suggest that one of the major organs affected by an unfavourable prenatal environment is the kidney. Many of the factors that can affect fetal renal development (i.e. exposure to excess glucocorticoids, insufficient vitamin A, protein/calorie malnutrition (in rats) and alterations in the intrarenal renin angiotensinogen system), also produce hypertension in the adult animal. When nephron number is compromised during kidney development, maladaptive functional changes occur and can lead, eventually, to hypertension and/or renal disease. Surprisingly, it is during the very earliest stages of kidney development that the vulnerability to these effects occurs.

Ovine fetuses exposed to high concentrations of synthetic (dexamethasone, D) or naturally occurring glucocorticoids (cortisol, F) in utero during early gestation develop high blood pressure in adulthood. To investigate potential mechanisms involved, we examined the role of the renal renin-angiotensin system (RAS). Ewes were infused with isotonic saline (S, n = 11), D (n = 12, 0.48 mg/h), or F (n = 5, 5 mg/h) for 48 h between d 26 and 28 of gestation (term = 150 d). Ewes carrying twins (S, n = 5; D, n = 6; F, n = 5) were killed at 130 d of gestation. The mRNA levels for angiotensinogen, the AT(1) receptor and AT(2) receptor, were increased in the fetal kidneys after D treatment. Prenatal infusions of F produced similar effects on the AT(1) receptor. Single fetuses (S, n = 6; D, n = 6) were cannulated and infused with angiotensin II for 3 d beginning at 127 d of gestation. Basal blood pressure was similar in both groups and increased similarly with angiotensin II infusion. However, increases in urine flow and glomerular filtration rate were significantly reduced and kidney weights increased in the D-treated group. These results indicate that treatment with D very early in gestation causes significant alterations in the RAS in the fetal kidney 100 d later with functional consequences. Changes in the RAS in the developing kidney may be an important mechanism in the development of adult disease.