Low birth weight serves as a crude proxy for impaired growth during fetal life and indicates a failure for the fetus to achieve its full growth potential. Low birth weight can occur in response to numerous etiologies that include complications during pregnancy, poor prenatal care, parental smoking, maternal alcohol consumption or stress. Numerous epidemiological and experimental studies demonstrate that birth weight is inversely associated with blood pressure and coronary heart disease. Sex and age impact the developmental programming of hypertension. In addition, impaired growth during fetal life also programs enhanced vulnerability to a secondary insult. Macrosomia, which occurs in response to maternal obesity, diabetes and excessive weight gain during gestation, is also associated with increased cardiovascular risk. Yet, the exact mechanisms that permanently change the structure, physiology and endocrine health of an individual across their lifespan following altered growth during fetal life are not entirely clear. Transmission of increased risk from one generation to the next in the absence of an additional prenatal insult indicates an important role for epigenetic processes. Experimental studies also indicate that the sympathetic nervous system, the renin angiotensin system, increased production of oxidative stress and increased endothelin play an important role in the developmental programming of blood pressure in later life. Thus, this review will highlight how adverse influences during fetal life and early development program an increased risk for cardiovascular disease including high blood pressure and provide an overview of the underlying mechanisms that contribute to the fetal origins of cardiovascular pathology.

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 versus 117±4 mmHg, 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 versus 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 versus 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 versus control). Due to 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.

Hypertension is a risk factor for cardiovascular disease, the leading cause of death worldwide. Although multiple factors contribute to the pathogenesis of hypertension, studies by Dr. David Barker reporting an inverse relationship between birth weight and blood pressure led to the hypothesis that slow growth during fetal life increases blood pressure and the risk for cardiovascular disease in later life. It is now recognized that growth during infancy and childhood in addition to exposure to adverse influences during fetal life contribute to the developmental programming of increased cardiovascular risk. Numerous epidemiological studies support the link between influences during early life with later cardiovascular health; experimental models provide proof of principle and indicate that numerous mechanisms contribute to the developmental origins of chronic disease. Sex impacts the severity of cardiovascular risk in experimental models of developmental insult. Yet, few studies examine the influence of sex on blood pressure and cardiovascular health in low birth weight men and women. Fewer still assess how aging impacts sex differences in programmed cardiovascular risk. Thus, the aim of this review is to highlight current data regarding sex differences in the developmental programming of blood pressure and cardiovascular disease.

cental 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 growthrestricted 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 Ϫ1 ·day Ϫ1 ) for 1 wk. Baseline blood pressures were similar between growthrestricted (112 Ϯ 3 mmHg) and control (110 Ϯ 2 mmHg) rats; however, an enhanced pressor response to acute ANG II (100 ng·kg Ϫ1 ·min Ϫ1 for 30 min) was observed in growth-restricted (160 Ϯ 2 mmHg) vs. control (136 Ϯ 2 mmHg; P Ͻ 0.05) rats. Castration abolished the enhanced pressor response to acute ANG II in growthrestricted (130 Ϯ 2 mmHg) rats with no significant effect on blood pressure in controls (130 Ϯ 2 mmHg). Blood pressure was increased to a similar extent above baseline in response to acute phenylephrine (100 g/min) in control (184 Ϯ 5 mmHg) and growth-restricted (184 Ϯ 8 mmHg) rats, suggesting the enhanced pressor response in growthrestricted 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. sex steroids; blood pressure; developmental programming ADVERSE INFLUENCES DURING early life can lead to an increased risk for cardiovascular and renal disease (4, 21). Using a model of reduced uterine perfusion in the pregnant rat, our laboratory has begun to elucidate the mechanisms linking intrauterine growth restriction (IUGR) and blood pressure (1). We previously reported that male growth-restricted offspring from reduced uterine perfusion dams exhibit a marked increase in arterial pressure in adulthood that is associated with a marked increase in intrarenal renin and angiotensinogen mRNA expression, and a marked increase in renal angiotensin I-converting enzyme (ACE) activity (9). However, despite these increases in intrarenal renin and angiotensinogen mRNA expression and intrarenal ACE activity, expression of intrarenal ANG II and its receptor, AT 1 R, are similar in hypertensive male growth-restricted rats compared with normotensive age-matched male control rats (9). Moreover, plasma renin activity, plasma renin substrate, and serum ACE activity are not altered in adult male growth-restricted rats relative to control (9, 22) suggesting that inappropriate activation of the systemic renin angiotensin system (RAS) is not obse...