A mechanistic look at the effects of adversity early in life on cardiovascular disease risk during adulthood

Loria, Analia S.; Ho, Dao H.; Pollock, Jennifer S.

doi:10.1111/apha.12189

Cited by 45 publications

(38 citation statements)

References 124 publications

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“…The studies by Pollock and coworkers showed that rats exposed to this ELS had normal resting BP as adults but exaggerated acute pressor (vasoconstrictor) responses to norepinephrine (37) and augmented hypertensive responses to chronic angiotensin II infusion (39,40). Their studies implicated changes in arterial and kidney function in the relationship between ELS and adult hypertension (38). In the present study, we observed that PND21 MA1s from rats exposed to MS stress at PND2-14 had increased force to KCl depolarization, to PE, and to calcium in permeabilized preparations, all consistent with the acceleration of the functional maturation of these arteries.…”

Section: Discussionmentioning

confidence: 99%

The stress of maternal separation causes misprogramming in the postnatal maturation of rat resistance arteries

Reho

Fisher

2015

American Journal of Physiology-Heart and Circulatory Physiology

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Reho JJ, Fisher SA. The stress of maternal separation causes misprogramming in the postnatal maturation of rat resistance arteries. Am J Physiol Heart Circ Physiol 309: H1468-H1478, 2015. First published September 14, 2015; doi:10.1152/ajpheart.00567.2015.-We examined the effect of stress in the first 2 wk of life induced by brief periods of daily maternal separation on developmental programming of rat small resistance mesenteric arteries (MAs). In MAs of littermate controls, mRNAs encoding mediators of vasoconstriction, including the ␣ 1a-adrenergic receptor, smooth muscle myosin heavy chain, and CPI-17, the inhibitory subunit of myosin phosphatase, increased from after birth through sexual [postnatal day (PND) 35] and full maturity, up to ϳ80-fold, as measured by quantitative PCR. This was commensurate with two-to fivefold increases in maximum force production to KCl depolarization, calcium, and the ␣-adrenergic agonist phenylephrine, and increasing systolic blood pressure. Rats exposed to maternal separation stress as neonates had markedly accelerated trajectories of maturation of arterial contractile gene expression and function measured at PND14 or PND21 (weaning), 1 wk after the end of the stress protocol. This was suppressed by the ␣-adrenergic receptor blocker terazosin (0.5 mg·kg ip Ϫ1 ·day Ϫ1 ), indicating dependence on stress activation of sympathetic signaling. Due to the continued maturation of MAs in control rats, by sexual maturity (PND35) and into adulthood, no differences were observed in arterial function or response to a second stressor in rats stressed as neonates. Thus early life stress misprograms resistance artery smooth muscle, increasing vasoconstrictor function and blood pressure. This effect wanes in later stages, suggesting plasticity during arterial maturation. Further studies are indicated to determine whether stress in different periods of arterial maturation may cause misprogramming persisting through maturity and the potential salutary effect of ␣-adrenergic blockade in suppression of this response. OBSERVATION OF A STRONG GEOGRAPHICAL relationship between mortality from ischemic heart disease in the 1970s and infant mortality rates one-half a century earlier (5) formed the basis for the hypothesis that cardiovascular mortality in the adult is developmentally programmed (4). This relationship was confirmed in subsequent studies and extended to a variety of developmental stressors. Children raised in low socioeconomic status families under harsh and stressful conditions predicted increasing blood pressure (BP) over time and increased vascular reactivity to stress [CARDIA study (9,34), reviewed in Ref. 56]. In the Bogalusa Heart (3) and other studies, those with the greatest trajectory of BP increase during childhood and adolescence had several-fold higher prevalence of hypertension (r ϳ0.4, see Ref. 10 for meta-analysis) and increased cardiovascular mortality as adults (42). A natural human experiment was that of Finnish children voluntarily separated from their parents during Wo...

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Section: Discussionmentioning

confidence: 99%

The stress of maternal separation causes misprogramming in the postnatal maturation of rat resistance arteries

Reho

Fisher

2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…ELS can significantly modulate components of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) system in rodents (20). Specifically, rodents that have been subjected to maternal separation before weaning show altered circulating plasma corticosterone levels, increased HPA axis responsiveness to stressors, altered hippocampal glucocorticoid receptor density, increased corticotropin-releasing factor expression in hypothalamus, and decreased serotonin transporter and tryptophan hydrolyase expression in Table 2 for statistical analyses (n ϭ 5-7 per group).…”

Section: Discussionmentioning

confidence: 99%

Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood

Burch

Musall

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Early life stress (ELS) is a risk for cardiovascular disease in adulthood although very little mechanistic insight is available. Because oxidative stress and endothelial dysfunction are major contributors to cardiovascular risk, we hypothesized that ELS induces endothelial dysfunction in adult male mice via increased superoxide production. Studies employed a mouse model of ELS, maternal separation with early weaning (MSEW), in which litters were separated from the dam for 4 h/day [postnatal days (PD) 2-5] and 8 h/day (PD6-16), and weaned at PD17. Control litters remained undisturbed until weaning at PD21. When compared with control mice, thoracic aortic rings from adult male MSEW mice displayed significant endothelial dysfunction that was reversed by the superoxide scavenger, polyethylene glycol-superoxide dismutase (PEG-SOD). PEG-SOD-inhibitable superoxide production by aortae from MSEW mice was significantly greater than observed in control aortae, although unaffected by nitric oxide synthase inhibition, suggesting that uncoupled nitric oxide synthase was not responsible for the accelerated superoxide production. Aortic SOD expression, plasma SOD activity, and total antioxidant activity were similar in MSEW and control mice, indicating unaltered antioxidant capacity in MSEW mice. Increased expression of the NADPH oxidase subunits, NOX2 and NOX4, was evident in the aortae of MSEW mice. Moreover, endothelial dysfunction and superoxide production in MSEW mice was reversed with the NADPH oxidase inhibitor, apocynin, indicating increased NADPH oxidase-dependent superoxide production and endothelial dysfunction. The finding that MSEW induces superoxide production and endothelial dysfunction in adult mice may provide a mechanistic link between ELS and adult cardiovascular disease risk.

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“…Thus, sensitivity to vasoactive factor Ang II is enhanced following this developmental insult. Female ELS offspring exhibit a delay in the development of Ang II-induced hypertension relative to male ELS (Figure 7) (115) Furthermore, the degree of Ang II-induced hypertension is attenuated in female ELS offspring compared to male ELS offspring (Figure 7) (115) indicating that sex impacts the programming of CV risk in this model of ELS. Therefore, females in this model, like that observed in models induced by nutritional insults, are protected to some degree relative to their male littermates.…”

Section: History and Etiology Of The Fetal Origins Of Cardiovascular DImentioning

confidence: 96%

“…However, chronic stress prior to conception increases the risk of low birth weight (201). In addition, psychosocial stress in early life can impact later CV and metabolic health (For review, see 115). The mechanisms that contribute to the racial disparities in the prevalence of low birth weight are not clear.…”

Section: History and Etiology Of The Fetal Origins Of Cardiovascular DImentioning

confidence: 99%

“…However, absolute risk for coronary heart disease is increased in low birth weight men in young adulthood relative to age-matched low birth weight women suggesting that sex may impact the increased risk for CV disease that originates in early life (223). Many models of fetal and developmental programming exhibit a sex difference in blood pressure with female offspring protected to a greater degree relative to male counterparts (3, 21, 37, 115, 132, 151, 242; for an extensive review see 83). Males are more susceptible to the development of hypertension in models of fetal undernutrition, an observation noted in the rat (241), and the sheep (62).…”

Section: The Underlying Mechanisms That Program An Increase In Cardiomentioning

confidence: 99%

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Fetal Programming and Cardiovascular Pathology

Alexander

Dasinger

Intapad

2015

Comprehensive Physiology

184

144

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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.

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A mechanistic look at the effects of adversity early in life on cardiovascular disease risk during adulthood

Cited by 45 publications

References 124 publications

The stress of maternal separation causes misprogramming in the postnatal maturation of rat resistance arteries

The stress of maternal separation causes misprogramming in the postnatal maturation of rat resistance arteries

Early life stress in male mice induces superoxide production and endothelial dysfunction in adulthood

Fetal Programming and Cardiovascular Pathology

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