John Henry Dasinger

Fetal Programming and Cardiovascular Pathology

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.

Renal Denervation Abolishes the Age-Dependent Increase in Blood Pressure in Female Intrauterine Growth-Restricted Rats at 12 Months of Age

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.

Enhanced sensitivity to acute angiotensin II is testosterone dependent in adult male growth-restricted offspring.

Placental 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 growth-restricted 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(-1).day(-1)) for 1 wk. Baseline blood pressures were similar between growth-restricted (112 +/- 3 mmHg) and control (110 +/- 2 mmHg) rats; however, an enhanced pressor response to acute ANG II (100 ng.kg(-1).min(-1) for 30 min) was observed in growth-restricted (160 +/- 2 mmHg) vs. control (136 +/- 2 mmHg; P < 0.05) rats. Castration abolished the enhanced pressor response to acute ANG II in growth-restricted (130 +/- 2 mmHg) rats with no significant effect on blood pressure in controls (130 +/- 2 mmHg). Blood pressure was increased to a similar extent above baseline in response to acute phenylephrine (100 microg/min) in control (184 +/- 5 mmHg) and growth-restricted (184 +/- 8 mmHg) rats, suggesting the enhanced pressor response in growth-restricted 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.

Gender differences in developmental programming of cardiovascular diseases.

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 increased 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, contributes to the developmental programming of increased cardiovascular risk. Numerous epidemiological studies support the link between influences during early life and later cardiovascular health; experimental models provide proof of principle and indicate that numerous mechanisms contribute to the developmental origins of chronic disease. Sex has an impact on 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 the impact of ageing on sex differences in programmed cardiovascular risk. Thus, the aim of the present review is to highlight current data about sex differences in the developmental programming of blood pressure and cardiovascular disease.

Sex Differences in the Developmental Origins of Cardiovascular Disease

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.

Effect of low birth weight on women's health.

PURPOSE The theory of the developmental origins of health and disease hypothesizes that low birth weight (≤5.5 lb) indicative of poor fetal growth is associated with an increased risk of chronic, noncommunicable disease in later life, including hypertension, type 2 diabetes mellitus, and osteoporosis. Whether women are at greater risk than men is not clear. Experimental studies that mimic the cause of slow fetal growth are being used to examine the underlying mechanisms that link a poor fetal environment with later chronic disease and investigate how sex and age affect programmed risk. Thus, the aims of this review are to summarize the current literature related to the effect of low birth weight on womens health and provide insight into potential mechanisms that program increased risk of chronic disease across the lifespan. METHODS A search of PubMed was performed with the keywords low birth weight, womens health, female, and sex differences; additional terms included blood pressure, hypertension, renal, cardiovascular, obesity, glucose intolerance, type 2 diabetes, osteoporosis, bone health, reproductive senescence, menopause, and aging. FINDINGS The major chronic diseases associated with low birth weight include high blood pressure and cardiovascular disease, impaired glucose homeostasis and type 2 diabetes, impaired bone mass and osteoporosis, and early reproductive aging. IMPLICATIONS Low birth weight increases the risk of chronic disease in men and women. Low birth weight is also associated with increased risk of early menopause. Further studies are needed to fully address the effect of sex and age on the developmental programming of adult health and disease in women across their lifespan.

Developmental Programming of Hypertension: Physiological Mechanisms

Epidemiological studies indicate that the origins of high blood pressure initiates in fetal life.1–3 Recent reviews highlight a role for numerous factors in the pathogenesis of the developmental programming of hypertension including epigenetic processes, glucocorticoids, reduced nephron number, activation of the sympathetic nervous system, and the renin–angiotensin system (RAS) and endothelial dysfunction.4–7 Studies published in Hypertension and other journals highlight the complexity of cardiovascular risk that has its origins in fetal life. The purpose of this minireview is to present an update on recent studies in Hypertension that investigate the underlying mechanisms that contribute to the developmental programming of hypertension and increased risk for cardiovascular disease. Barker8 first proposed the theory of the fetal origins of coronary heart disease based on the hypothesis that adaptive responses by the fetus to maternal undernutrition would enhance survival to birth at the expense of later cardiovascular health. The first animal studies to investigate the Barker hypothesis utilized rodent models to demonstrate that maternal undernutrition during gestation programs an increase in blood pressure in the offspring.9 Based on previous studies indicating a role for the renal nerves in experimental models of low birth weight,10,11 Mizuno et al12 proposed that increased blood pressure in protein-restricted offspring would be associated with an increase in baseline measure of renal sympathetic nerve activity (SNA). Although baseline measurement of renal SNA under anesthesia did not differ in male protein-restricted offspring versus male control at 4 to 5 months of age, renal SNA was significantly elevated in response to a secondary hit of physical stress in association with a greater blood pressure response12 indicating a role for an increase in renal SNA in the developmental programming of increased blood pressure and cardiovascular risk. Chronic systemic blockade of …

Chronic Blockade of the Androgen Receptor Abolishes Age-Dependent Increases in Blood Pressure in Female Growth-Restricted Rats

Intrauterine growth restriction induced via placental insufficiency programs a significant increase in blood pressure at 12 months of age in female growth-restricted rats that is associated with early cessation of estrous cyclicity, indicative of premature reproductive senescence. In addition, female growth-restricted rats at 12 months of age exhibit a significant increase in circulating testosterone with no change in circulating estradiol. Testosterone is positively associated with blood pressure after menopause in women. Thus, we tested the hypothesis that androgen receptor blockade would abolish the significant increase in blood pressure that develops with age in female growth-restricted rats. Mean arterial pressure was measured in animals pretreated with and without the androgen receptor antagonist, flutamide (8 mg/kg/day, SC for 2 weeks). Flutamide abolished the significant increase in blood pressure in growth-restricted rats relative to control at 12 months of age. To examine the mechanism(s) by which androgens contribute to increased blood pressure in growth-restricted rats, blood pressure was assessed in rats untreated or treated with enalapril (250 mg/L for 2 weeks). Enalapril eliminated the increase in blood pressure in growth-restricted relative to vehicle- and flutamide-treated controls. Furthermore, the increase in medullary angiotensin type 1 receptor mRNA expression was abolished in flutamide-treated growth-restricted relative to untreated counterparts and controls; cortical angiotensin-converting enzyme mRNA expression was reduced in flutamide-treated growth-restricted versus untreated counterparts. Thus, these data indicate that androgens, via activation of the renin–angiotensin system, are important mediators of increased blood pressure that develops by 12 months of age in female growth-restricted rats.

Glucose intolerance develops prior to increased adiposity and accelerated cessation of estrous cyclicity in female growth-restricted rats

Background:The incidence of metabolic disease increases in early menopause. Low birth weight influences the age at menopause. Thus, this study tested the hypothesis that intrauterine growth restriction programs early reproductive aging and impaired glucose homeostasis in female rats.Methods:Estrous cyclicity, body composition, and glucose homeostasis were determined in female control and growth-restricted rats at 6 and 12 mo of age; sex steroids at 12 mo.Results:Glucose intolerance was present at 6 mo of age prior to cessation of estrous cyclicity and increased adiposity in female growth-restricted rats. However, female growth-restricted rats exhibited persistent estrus and a significant increase in adiposity, fasting glucose, and testosterone at 12 mo of age (P < 0.05). Insulin release in response to a glucose challenge was blunted in conjunction with a reduction in protein expression of pancreatic glucose transporter type 2 and estrogen receptor-α at 12 mo of age in female growth-restricted rats (P < 0.05).Conclusion:This study demonstrated that slow fetal growth programmed glucose intolerance that developed prior to early estrous acyclicity; yet, fasting glucose levels were elevated in conjunction with increased adiposity, accelerated cessation of estrous cyclicity and a shift toward testosterone excess at 12 mo of age in female growth-restricted rats.

Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring

Placental insufficiency programs an increase in blood pressure associated with a twofold increase in serum testosterone in male growth-restricted offspring at 4 mo of age. Population studies indicate that the inverse relationship between birth weight and blood pressure is amplified with age. Thus, we tested the hypothesis that intrauterine growth restriction programs an age-related increase in blood pressure in male offspring. Growth-restricted offspring retained a significantly higher blood pressure at 12 but not at 18 mo of age compared with age-matched controls. Blood pressure was significantly increased in control offspring at 18 mo of age relative to control counterparts at 12 mo; however, blood pressure was not increased in growth-restricted at 18 mo relative to growth-restricted counterparts at 12 mo. Serum testosterone levels were not elevated in growth-restricted offspring relative to control at 12 mo of age. Thus, male growth-restricted offspring no longer exhibited a positive association between blood pressure and testosterone at 12 mo of age. Unlike hypertension in male growth-restricted offspring at 4 mo of age, inhibition of the renin-angiotensin system with enalapril (250 mg/l for 2 wk) did not abolish the difference in blood pressure in growth-restricted offspring relative to control counterparts at 12 mo of age. Therefore, these data suggest that intrauterine growth restriction programs an accelerated age-related increase in blood pressure in growth-restricted offspring. Furthermore, this study suggests that the etiology of increased blood pressure in male growth-restricted offspring at 12 mo of age differs from that at 4 mo of age.