Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct

Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cere...

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Autores principales:	Zhenzhou Li, Heather L. McConnell, Teresa L. Stackhouse, Martin M. Pike, Wenri Zhang, Anusha Mishra
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	neurovascular coupling stroke cerebral blood flow capillaries microvasculature Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/c7eaccd7ab43402384337a43bbf111d8
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spelling	oai:doaj.org-article:c7eaccd7ab43402384337a43bbf111d82021-11-08T05:24:40ZIncreased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct1662-510210.3389/fncel.2021.762843https://doaj.org/article/c7eaccd7ab43402384337a43bbf111d82021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fncel.2021.762843/fullhttps://doaj.org/toc/1662-5102Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by ∼75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-hydroxyeicosatetraenoic acid (20-HETE), either by inhibiting its synthetic enzyme CYP450 ω-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of ω-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of endoperoxide 4 (EP4) receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of ω-hydroxylases normalized 20-HETE levels in vivo and increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying capillary neurovascular coupling impairment after stroke. Our results suggest that the brain’s energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that ω-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.Zhenzhou LiZhenzhou LiHeather L. McConnellTeresa L. StackhouseMartin M. PikeWenri ZhangAnusha MishraAnusha MishraFrontiers Media S.A.articleneurovascular couplingstrokecerebral blood flowcapillariesmicrovasculatureNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Cellular Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neurovascular coupling stroke cerebral blood flow capillaries microvasculature Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	neurovascular coupling stroke cerebral blood flow capillaries microvasculature Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Zhenzhou Li Zhenzhou Li Heather L. McConnell Teresa L. Stackhouse Martin M. Pike Wenri Zhang Anusha Mishra Anusha Mishra Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct
description	Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by ∼75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-hydroxyeicosatetraenoic acid (20-HETE), either by inhibiting its synthetic enzyme CYP450 ω-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of ω-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of endoperoxide 4 (EP4) receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of ω-hydroxylases normalized 20-HETE levels in vivo and increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying capillary neurovascular coupling impairment after stroke. Our results suggest that the brain’s energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that ω-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.
format	article
author	Zhenzhou Li Zhenzhou Li Heather L. McConnell Teresa L. Stackhouse Martin M. Pike Wenri Zhang Anusha Mishra Anusha Mishra
author_facet	Zhenzhou Li Zhenzhou Li Heather L. McConnell Teresa L. Stackhouse Martin M. Pike Wenri Zhang Anusha Mishra Anusha Mishra
author_sort	Zhenzhou Li
title	Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct
title_short	Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct
title_full	Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct
title_fullStr	Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct
title_full_unstemmed	Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct
title_sort	increased 20-hete signaling suppresses capillary neurovascular coupling after ischemic stroke in regions beyond the infarct
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/c7eaccd7ab43402384337a43bbf111d8
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Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct

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