RT Journal Article
SR Electronic
T1 Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.25.457547
DO 10.1101/2021.08.25.457547
A1 Zhenzhou Li
A1 Heather L. McConnell
A1 Teresa L. Stackhouse
A1 Martin M. Pike
A1 Wenri Zhang
A1 Anusha Mishra
YR 2021
UL http://biorxiv.org/content/early/2021/08/27/2021.08.25.457547.abstract
AB 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 StatementThe authors have declared no competing interest.