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.

The Developmental Origins of Health and Disease (DOHaD) proposes that adverse events during early life program an increased risk for cardiovascular disease. Experimental models provide proof of concept but also indicate that insults during early life program sex differences in adult blood pressure and cardiovascular risk. This review will highlight the potential mechanisms that contribute to the etiology of sex differences in the developmental programming of cardiovascular disease.

Experimental models of developmental programming provide proof of concept and support Barker’s original findings that link birth weight and blood pressure. Many experimental models of developmental insult demonstrate a sex difference with male offspring exhibiting a higher blood pressure in young adulthood relative to their age-matched female counterparts. It is well recognized that men exhibit a higher blood pressure relative to age-matched women prior to menopause. Yet, whether this sex difference is noted in individuals born with low birth weight is not clear. Sex differences in the developmental programming of blood pressure may originate from innate sex-specific differences in expression of the renin angiotensin system that occur in response to adverse influences during early life. Sex differences in the developmental programming of blood pressure may also involve the influence of the hormonal milieu on regulatory systems key to the long term control of blood pressure such as the renin angiotensin system in adulthood. In addition, the sex difference in blood pressure in offspring exposed to a developmental insult may involve innate sex differences in oxidative status or the endothelin system, or may be influenced by age-dependent changes in the developmental programming of cardiovascular risk factors such as adiposity. Therefore, this review will highlight findings from different experimental models to provide the current state of knowledge related to the mechanisms that contribute to the etiology of sex differences in the developmental programming of blood pressure and hypertension.