title: Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation.
abstract: OBJECTIVE
  The endothelium maintains vascular homeostasis through the release of endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH). The balance in EDH : EDRF is disturbed in cardiovascular disease and may also be susceptible to developmental conditioning through exposure to an adverse uterine environment to predispose to later risk of hypertension and vascular disease.
  
  
  METHODS
  Developmentally conditioned changes in EDH : EDRF signalling pathways were investigated in cremaster arterioles (18-32  μm diameter) and third-order mesenteric arteries of adult male mice offspring of dams fed either a fat-rich (high fat, HF, 45% energy from fat) or control (C, 10% energy from fat) diet. After weaning, offspring either continued on high fat or were placed on control diets to give four dietary groups (C/C, HF/C, C/HF, and HF/HF) and studied at 15 weeks of age.
  
  
  RESULTS
  EDH via intermediate (IKCa) and small (SKca) conductance calcium-activated potassium channels contributed less than 10% to arteriolar acetylcholine-induced relaxation in in-situ conditioned HF/C offspring compared with ∼60% in C/C (P < 0.01). The conditioned reduction in EDH signalling in HF/C offspring was reversed in offspring exposed to a high-fat diet both before and after weaning (HF/HF, 55%, P < 0.01 vs. HF/C). EDH signalling was unaffected in arterioles from C/HF offspring. The changes in EDH : EDRF were associated with altered endothelial cell expression and localization of IKCa channels.
  
  
  CONCLUSIONS
  This is the first evidence that EDH-mediated microvascular relaxation is susceptible to an adverse developmental environment through down-regulation of the IKCa signalling pathway. Conditioned offspring exposed to a 'second hit' (HF/HF) exhibit adaptive vascular mechanisms to preserve dilator function.
authors.affiliation: aVascular Research Group bBone and Joint Research Group, Institute of Developmental Sciences cFaculty of Medicine, Biomedical Imaging Unit, University of Southampton, Southampton dCardiovascular Division, BHF Centre of Research Excellence, School of Medicine, King's College London, London, United Kingdom *Rebecca Stead and Moji G. Musa contributed equally to the writing of this article.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stead
authors.forename: Moji G
authors.initials: MG
authors.lastname: Musa
authors.forename: Claire L
authors.initials: CL
authors.lastname: Bryant
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lanham
authors.forename: David A
authors.initials: DA
authors.lastname: Johnston
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
authors.forename: Christopher
authors.initials: C
authors.lastname: Torrens
authors.forename: Paul A
authors.initials: PA
authors.lastname: Fraser
authors.forename: Geraldine F
authors.initials: GF
authors.lastname: Clough
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D001685:Biological Factors / Q000378:metabolism*; D004032:Diet; D059305:Diet, High-Fat; D015536:Down-Regulation; D005260:Female; D006973:Hypertension; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D009638:Norepinephrine / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D012333:RNA, Messenger; D051640:Small-Conductance Calcium-Activated Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000109:Acetylcholine; D009638:Norepinephrine