Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation
Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation
OBJECTIVES: 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.
CONCLUSION: 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.
Acetylcholine/pharmacology, Animals, Arterioles/drug effects, Biological Factors/metabolism, Diet, Diet, High-Fat, Down-Regulation, Female, Hypertension, Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism, Male, Mesenteric Arteries/drug effects, Mice, Nitric Oxide, Nitric Oxide Synthase Type III/genetics, Norepinephrine/pharmacology, Pregnancy, Prenatal Exposure Delayed Effects/metabolism, RNA, Messenger/metabolism, Real-Time Polymerase Chain Reaction, Small-Conductance Calcium-Activated Potassium Channels/metabolism, Vasoconstriction/drug effects, Vasoconstrictor Agents/pharmacology, Vasodilation/drug effects, Vasodilator Agents/pharmacology
452-63; discussion 463
Stead, Rebecca
a481dba4-a1ed-4d98-ad59-a6457d069928
Musa, Moji G
cee8b9cf-79d4-4bc3-9890-3192bfd0c8b2
Bryant, Claire L
4dc0c51e-ac8c-46e4-a541-0de4832f2452
Lanham, Stuart A
28fdbbef-e3b6-4fdf-bd0f-4968eeb614d6
Johnston, David A
b41163c9-b9d2-425c-af99-2a357204014e
Reynolds, Richard
759e6564-c400-49c4-b245-2e6a85583947
Torrens, Christopher
15a35713-0651-4249-8227-5901e2cfcd22
Fraser, Paul A
2ca9aa50-7435-4f76-9938-f1ff84ae744e
Clough, Geraldine F
9f19639e-a929-4976-ac35-259f9011c494
1 March 2016
Stead, Rebecca
a481dba4-a1ed-4d98-ad59-a6457d069928
Musa, Moji G
cee8b9cf-79d4-4bc3-9890-3192bfd0c8b2
Bryant, Claire L
4dc0c51e-ac8c-46e4-a541-0de4832f2452
Lanham, Stuart A
28fdbbef-e3b6-4fdf-bd0f-4968eeb614d6
Johnston, David A
b41163c9-b9d2-425c-af99-2a357204014e
Reynolds, Richard
759e6564-c400-49c4-b245-2e6a85583947
Torrens, Christopher
15a35713-0651-4249-8227-5901e2cfcd22
Fraser, Paul A
2ca9aa50-7435-4f76-9938-f1ff84ae744e
Clough, Geraldine F
9f19639e-a929-4976-ac35-259f9011c494
Stead, Rebecca, Musa, Moji G, Bryant, Claire L, Lanham, Stuart A, Johnston, David A, Reynolds, Richard, Torrens, Christopher, Fraser, Paul A and Clough, Geraldine F
(2016)
Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation.
Journal of Hypertension, 34 (3), .
(doi:10.1097/HJH.0000000000000833).
(PMID:26682783)
Abstract
OBJECTIVES: 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.
CONCLUSION: 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.
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Developmental_conditioning_of_endothelium_derived.14
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Accepted/In Press date: 20 November 2015
e-pub ahead of print date: 17 December 2015
Published date: 1 March 2016
Keywords:
Acetylcholine/pharmacology, Animals, Arterioles/drug effects, Biological Factors/metabolism, Diet, Diet, High-Fat, Down-Regulation, Female, Hypertension, Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism, Male, Mesenteric Arteries/drug effects, Mice, Nitric Oxide, Nitric Oxide Synthase Type III/genetics, Norepinephrine/pharmacology, Pregnancy, Prenatal Exposure Delayed Effects/metabolism, RNA, Messenger/metabolism, Real-Time Polymerase Chain Reaction, Small-Conductance Calcium-Activated Potassium Channels/metabolism, Vasoconstriction/drug effects, Vasoconstrictor Agents/pharmacology, Vasodilation/drug effects, Vasodilator Agents/pharmacology
Organisations:
Faculty of Medicine
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Local EPrints ID: 392059
URI: http://eprints.soton.ac.uk/id/eprint/392059
ISSN: 0263-6352
PURE UUID: 5da6ff98-3f69-4ca4-88c1-024221676b73
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Date deposited: 14 Apr 2016 09:33
Last modified: 15 Mar 2024 03:29
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Contributors
Author:
Rebecca Stead
Author:
Moji G Musa
Author:
Claire L Bryant
Author:
Stuart A Lanham
Author:
David A Johnston
Author:
Richard Reynolds
Author:
Christopher Torrens
Author:
Paul A Fraser
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