title: The stress of maternal separation causes misprogramming in the postnatal maturation of rat resistance arteries.
abstract: 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 α1a-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 ∼80-fold, as measured by quantitative PCR. This was commensurate with two- to fivefold increases in maximum force production to KCl depolarization, calcium, and the α-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 α-adrenergic receptor blocker terazosin (0.5 mg·kg ip(-1)·day(-1)), 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 α-adrenergic blockade in suppression of this response.
authors.affiliation: Departments of Medicine (Cardiovascular Medicine) and Physiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: John J
authors.initials: JJ
authors.lastname: Reho
authors.affiliation: Departments of Medicine (Cardiovascular Medicine) and Physiology, University of Maryland School of Medicine, Baltimore, Maryland SFisher1@medicine.umaryland.edu.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Fisher
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D008426:Maternal Deprivation; D008638:Mesenteric Arteries / Q000254:growth & development / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000254:growth & development / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D009219:Myosin-Light-Chain Kinase / Q000235:genetics; D010656:Phenylephrine / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology; D054645:Protein Phosphatase 1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D009124:Muscle Proteins; D010750:Phosphoproteins; C491519:Ppp1r14a protein, rat; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; C041226:Terazosin; D009219:Myosin-Light-Chain Kinase; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D018995:Myosin Heavy Chains; D011224:Prazosin
keywords: development; smooth muscle; sympathetic; vasoconstriction; α-adrenergic