Early Life Stress Sensitizes Rats to Angiotensin II–Induced Hypertension and Vascular Inflammation in Adult Life

Loria, Analia S.; Pollock, David M.; Pollock, Jennifer S.

doi:10.1161/hypertensionaha.109.145391

Cited by 70 publications

(87 citation statements)

References 43 publications

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“…In rodents, maternal separation has been used to study the influence of chronic behavioral stress, and we reasoned that this model resembles, in part, an adverse environment during early life that may increase susceptibility to cardiovascular disease. Interestingly, the MS model does not appear to induce significant baseline differences in the cardiovascular phenotype in rats (33,47). Consistent with our report, several studies in rodents demonstrate that MS does not affect locomotor activity (4,19,27,45).…”

Section: Discussionsupporting

confidence: 91%

Early life stress downregulates endothelin receptor expression and enhances acute stress-mediated blood pressure responses in adult rats

Loria

D’Angelo

Pollock

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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We hypothesized that early life stress enhances endothelin (ET-1)-dependent acute stress responses in adulthood. We utilized a unique rat model, wildtype (WT) and ETB receptor-deficient spotting lethal (sl/sl) rats, as well as pharmacological blockade of ET receptors, in a model of early life stress, maternal separation (MS). MS was performed in male WT and sl/sl rats 3 h/day from day 2 to 14 of life. Acute air jet stress (AJS)-induced responses (elevation in blood pressure, plasma corticosterone, and plasma ET-1) were evaluated in adult MS rats compared with the nonhandled littermate (control) rats. MS significantly augmented the acute AJS-induced blood pressure response (area under the curve) in WT rats compared with control, while the AJS-induced pressor responses were similar in sl/sl MS and control rats. ET receptor blockade significantly blunted the AJS-induced pressor response in WT MS and control rats. Moreover, AJS-induced plasma corticosterone levels in control rats were sensitive to ET receptor blockade, yet, AJS did not alter plasma corticosterone levels in MS rats. MS significantly increased circulating ET-1 levels, and AJS-induced plasma ET-1 levels were similarly increased in control and MS rats. MS induced a significant downregulation in expression of ETA and ETB receptors in aortic tissue compared with control rats. These results indicate that early life stress reduced expression of ETA and ETB receptors, leading to alterations in the ET pathway, and an exaggerated acute stress-mediated pressor response in adulthood.early life stress; maternal separation; air jet stress; blood pressure; endothelin; corticosterone IN HUMANS, THERE IS A LARGE body of epidemiological evidence that early social experiences can promote phenotypic changes that persist in adult life (5,12,28). An adverse environment during early life increases the susceptibility to develop heart disease, as well as depression, drug abuse, obesity, and diabetes (21,24,32).Acute behavioral stress responses in adult life are influenced by early life maternal care in both humans (53) and rodents (36). Maternal separation is a widely used animal model of early life stress and chronic behavioral stress (20). Rat pups separated from their mothers daily for a prolonged period (up to 3 h) during the hyporesponsive period display abnormal anxiety-related behavior (41, 43), as well as increased acute behavioral and endocrine stress reactivity as adults (4,27,38,44).Individuals with increased susceptibility to stressors may also have an exacerbated rise in blood pressure (26). Acute stressors induce many physiological responses, and greater reactivity to stress or delayed poststress recovery predicts future cardiovascular disease risk (7), such as stroke (14), hypertension (37), and preclinical atherosclerosis (23,52). An acute stress-induced rise in blood pressure results from autonomic and neuroendocrine-mediated changes in cardiac contractility and peripheral vascular resistance (18). Particularly relevant to this study, acute stress is associa...

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Section: Discussionsupporting

confidence: 91%

Early life stress downregulates endothelin receptor expression and enhances acute stress-mediated blood pressure responses in adult rats

Loria

D’Angelo

Pollock

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Our study reports associations between early adversity and DNAm in adulthood in a non-Western, lower income setting. Furthermore, our findings are consistent with experimental animal models documenting durable effects of maternal separation on the regulation of inflammation (50)(51)(52).…”

Section: Discussionsupporting

confidence: 89%

Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood

McDade

Ryan

Jones

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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Chronic inflammation contributes to a wide range of human diseases, and environments in infancy and childhood are important determinants of inflammatory phenotypes. The underlying biological mechanisms connecting early environments with the regulation of inflammation in adulthood are not known, but epigenetic processes are plausible candidates. We tested the hypothesis that patterns of DNA methylation (DNAm) in inflammatory genes in young adulthood would be predicted by early life nutritional, microbial, and psychosocial exposures previously associated with levels of inflammation. Data come from a population-based longitudinal birth cohort study in metropolitan Cebu, the Philippines, and DNAm was characterized in whole blood samples from 494 participants (age 20–22 y). Analyses focused on probes in 114 target genes involved in the regulation of inflammation, and we identified 10 sites across nine genes where the level of DNAm was significantly predicted by the following variables: household socioeconomic status in childhood, extended absence of a parent in childhood, exposure to animal feces in infancy, birth in the dry season, or duration of exclusive breastfeeding. To evaluate the biological significance of these sites, we tested for associations with a panel of inflammatory biomarkers measured in plasma obtained at the same age as DNAm assessment. Three sites predicted elevated inflammation, and one site predicted lower inflammation, consistent with the interpretation that levels of DNAm at these sites are functionally relevant. This pattern of results points toward DNAm as a potentially important biological mechanism through which developmental environments shape inflammatory phenotypes across the life course.

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“…Neonatal rats were subject to the MS stress protocol, as previously described (35,40), with litter sizes culled to 10 pups/litter. Neonates were separated from their mothers and placed in a heated cage (30°C) for 3 h/day from PND2-14.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies by Pollock and coworkers showed that rats exposed to this ELS had normal resting BP as adults, but exaggerated acute pressor responses to norepinephrine (37) and 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).…”

Section: There Is Increasing Interest In Developmental Programming Ofmentioning

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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Early Life Stress Sensitizes Rats to Angiotensin II–Induced Hypertension and Vascular Inflammation in Adult Life

Cited by 70 publications

References 43 publications

Early life stress downregulates endothelin receptor expression and enhances acute stress-mediated blood pressure responses in adult rats

Early life stress downregulates endothelin receptor expression and enhances acute stress-mediated blood pressure responses in adult rats

Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood

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

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