Suttira Intapad

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.

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.

Sex differences in the developmental programming of hypertension

Experimental models of developmental programming provide proof of concept and support Barkers original findings that link birthweight 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 birthweight 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 aetiology of sex differences in the developmental programming of blood pressure and hypertension.

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.

Reduced uterine perfusion pressure induces hypertension in the pregnant mouse

Despite preeclampsia being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for its pathogenesis have yet to be fully elucidated. Growing evidence indicates that reduced uteroplacental perfusion and the resulting placental ischemia triggers the cascade of events leading to this maternal disorder. While the well-established rat model of reduced uterine perfusion pressure (RUPP) is providing invaluable insight into the etiology of preeclampsia, the aim of this study was to develop a mouse model of reduced uterine perfusion to expand mechanistic investigation by incorporation with novel gene-targeted mice. To accomplish this aim, a sham surgical procedure or a restriction of blood flow at the abdominal aorta and the ovarian arteries was initiated at day 13 of gestation in C57BL/6J mice. Mean arterial pressure measured in conscious, chronically instrumented mice was significantly elevated in the RUPP (120 ± 4 mmHg) compared with the sham (104 ± 4 mmHg) mice at day 18 of gestation (P < 0.01). Placental ischemia reduced fetal weights (0.95 ± 0.04 and 0.80 ± 0.02 g; RUPP vs. Sham, respectively; P < 0.02) and increased circulating levels of antiangiogenic soluble fms-related tyrosine kinases (sFlt)-1 (P < 0.05) in the RUPP at day 18 of gestation. Plasma concentrations of sFlt-1 are increased in preeclamptic patients and in response to reduced uterine perfusion in the rat. Thus, these results suggest that the mouse model of reduced uterine perfusion is applicable to facilitate novel mechanistic investigation into the etiology of hypertension that results from placental ischemia during pregnancy.

Long-term effect of phytoestrogens from Curcuma comosa Roxb. on vascular relaxation in ovariectomized rats.

Phytoestrogens have been implicated as promising therapeutic agents to treat the vascular impairment seen in menopausal women. The present study investigated the long-term effects of phytoestrogens from Curcuma comosa Roxb. on vascular relaxation of isolated thoracic aorta from ovariectomized (OVX) rats. Treatment of OVX rats for 12 weeks with C. comosa powder, hexane extract, and a novel phytoestrogen, diarylheptanoid-D3, [(3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol] prevented impairment of the endothelium-dependent relaxation response to acetylcholine in OVX, but not the endothelium-denude aortic ring relaxation in response to sodium nitroprusside. These data suggest that the vascular relaxation effect of C. comosa is mediated via endothelial cells. Treatment with D3 also increased endothelial nitric oxide synthase (eNOS) and estrogen receptor-α (ERα) protein expression in the aorta of OVX rats and suppressed elevated tumor necrosis factor-α (TNF-α) expression in OVX aortic rings. These results indicate that C. comosa treatment prevents impairment of vascular relaxation in estrogen-deficient animals via the ER-eNOS pathway as well as through its ability to promote an anti-inflammatory response.

Preterm Birth A Novel Risk Factor for Higher Blood Pressure in Later Life

See related article, pp 226–234 There is compelling epidemiological and experimental data that suggest that blood pressure in later life can be programmed by adverse influences during fetal life.1 Evidence for the theory of developmental programming of adult health and disease was first based on the geographical association of deaths from heart disease to death rates among newborn infants. This observation led to the hypothesis that undernutrition during fetal life permanently alters the physiology, structure, and metabolism of an individual leading to heart disease in later life.2 Poor fetal growth, the link to infant mortality, was also associated with systolic blood pressure (SBP), a known risk factor for heart disease; however, this association was independent of gestational age.3 In this issue of Hypertension , de Jong et al4 present their findings from a thorough and systematic review of the literature followed by a meta-analysis to determine whether preterm birth predicts a higher SBP in later life. Their results indicate that individuals born preterm have a higher SBP in later life than infants born at term (2.5 mm Hg).4 Although this difference in SBP is small, it is similar to the increase observed in studies linking birth weight and SBP,5 indicating that preterm birth, not unlike poor fetal growth with birth at term, may also …

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.