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Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct

View ORCID ProfileZhenzhou Li, View ORCID ProfileHeather L. McConnell, View ORCID ProfileTeresa L. Stackhouse, View ORCID ProfileMartin M. Pike, View ORCID ProfileWenri Zhang, View ORCID ProfileAnusha Mishra
doi: https://doi.org/10.1101/2021.08.25.457547
Zhenzhou Li
1Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR
2Department Anesthesiology, General Hospital of Ningxia Medical University, Ningxia, China
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Heather L. McConnell
3Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR
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Teresa L. Stackhouse
3Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR
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Martin M. Pike
4Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR
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Wenri Zhang
5Department of Anesthesiology and Peri-operative Medicine, Oregon Health & Science University, Portland, OR
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Anusha Mishra
1Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR
3Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR
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  • For correspondence: mishraa@ohsu.edu
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Abstract

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-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 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 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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 27, 2021.
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Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct
Zhenzhou Li, Heather L. McConnell, Teresa L. Stackhouse, Martin M. Pike, Wenri Zhang, Anusha Mishra
bioRxiv 2021.08.25.457547; doi: https://doi.org/10.1101/2021.08.25.457547
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Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct
Zhenzhou Li, Heather L. McConnell, Teresa L. Stackhouse, Martin M. Pike, Wenri Zhang, Anusha Mishra
bioRxiv 2021.08.25.457547; doi: https://doi.org/10.1101/2021.08.25.457547

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