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

Abstract

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...

Maternal separation enhances anticontractile perivascular adipose tissue function in male rats on a high-fat diet

“…Exposure to MatSep during postnatal life is not associated with increased body weight or blood pressure at baseline; however, this model exerts a long-lasting effect on ANG II-induced vasoconstriction in adult rats fed an ND ex vivo (38) and in vivo (36,37), yet MatSep does not alter circulating levels of ANG II peptide, plasma renin activity, and aldosterone in ND-fed rats. Contrary to what we observed, Reho et al (48) has reported that the effects of MatSep on the vascular dysfunction trajectory wanes from postnatal to adult life. However, a large body of literature has shown that the sensitization of the cardiovascular response depends upon strain, stimuli, duration, and timing of the stressor or diet [reviewed in (44)].…”

Effects of Neonatal Methamphetamine and Stress on Brain Monoamines and Corticosterone in Preweanling Rats

“…The effects of barren cage housing on NE and the sympathetic nervous system may be important in light of the current findings. Early life stress, as modeled by maternal separation during early development, induces a sensitization of the sympathetic nervous system (Loria et al 2013; Reho and Fisher 2015). For example, compared with controls, NE content is significantly increased in the spleen and adrenals of maternally separated offspring, and these rats display significantly greater increases in mean arterial pressure in response to NE administration, suggesting a sensitization of the sympathetic system by early life stress (Loria et al 2013).…”

Maternal Separation Induces Long-Term Alterations in the Cardiac Oxytocin Receptor and Cystathionine γ-Lyase Expression in Mice

“…This hypothesis is supported by studies in animal models showing that MS results in cardiac changes including cardiomyocyte hypertrophy as well as cardiac fibrosis [19]. More data is available showing that MS results in changes on the vascular level by misprogramming of resistance artery smooth muscles [20], increased vasoconstriction [21], and blood pressure [22,23]. These alterations are induced by superoxide production and endothelial dysfunction [24], inflammation [25], and sensitizing of the renal and sympathetic systems [26].…”