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Developmental conditioning of endothelium-derived hyperpolarizing factor (EDH) mediated vasorelaxation

Developmental conditioning of endothelium-derived hyperpolarizing factor (EDH) mediated vasorelaxation
Developmental conditioning of endothelium-derived hyperpolarizing factor (EDH) 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 [mu]m 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.
0263-6352
452-463
Stead, Rebecca
647602ed-d761-47a9-8a9c-b9ffdd43511c
Musa, Moji G.
cee8b9cf-79d4-4bc3-9890-3192bfd0c8b2
Bryant, Claire L.
4dc0c51e-ac8c-46e4-a541-0de4832f2452
Lanham, Stuart
28fdbbef-e3b6-4fdf-bd0f-4968eeb614d6
Johnston, David A.
33902f48-0d71-467c-b481-637b4d8a055b
Torrens, Christopher
15a35713-0651-4249-8227-5901e2cfcd22
Fraser, Paul A.
2ca9aa50-7435-4f76-9938-f1ff84ae744e
Clough, Geraldine
9f19639e-a929-4976-ac35-259f9011c494
Stead, Rebecca
647602ed-d761-47a9-8a9c-b9ffdd43511c
Musa, Moji G.
cee8b9cf-79d4-4bc3-9890-3192bfd0c8b2
Bryant, Claire L.
4dc0c51e-ac8c-46e4-a541-0de4832f2452
Lanham, Stuart
28fdbbef-e3b6-4fdf-bd0f-4968eeb614d6
Johnston, David A.
33902f48-0d71-467c-b481-637b4d8a055b
Torrens, Christopher
15a35713-0651-4249-8227-5901e2cfcd22
Fraser, Paul A.
2ca9aa50-7435-4f76-9938-f1ff84ae744e
Clough, Geraldine
9f19639e-a929-4976-ac35-259f9011c494

Stead, Rebecca, Musa, Moji G., Bryant, Claire L., Lanham, Stuart, Johnston, David A., Torrens, Christopher, Fraser, Paul A. and Clough, Geraldine (2016) Developmental conditioning of endothelium-derived hyperpolarizing factor (EDH) mediated vasorelaxation. Journal of Hypertension, 34 (3), 452-463. (doi:10.1097/HJH.0000000000000833). (PMID:26682783)

Record type: Article

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 [mu]m 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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Accepted/In Press date: 20 November 2015
e-pub ahead of print date: 17 December 2015
Published date: March 2016
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 392059
URI: http://eprints.soton.ac.uk/id/eprint/392059
ISSN: 0263-6352
PURE UUID: 5da6ff98-3f69-4ca4-88c1-024221676b73
ORCID for Stuart Lanham: ORCID iD orcid.org/0000-0002-4516-264X
ORCID for Geraldine Clough: ORCID iD orcid.org/0000-0002-6226-8964

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Date deposited: 14 Apr 2016 09:33
Last modified: 10 Dec 2019 01:53

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Contributors

Author: Rebecca Stead
Author: Moji G. Musa
Author: Claire L. Bryant
Author: Stuart Lanham ORCID iD
Author: David A. Johnston
Author: Christopher Torrens
Author: Paul A. Fraser

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