Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct.
Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct.
复制标题
DOI：
10.3389/fncel.2021.762843
复制
发表时间：
2021
影响因子：
5.3
通讯作者：
Mishra A
中科院分区：
文献类型：
--
作者：
Li Z;McConnell HL;Stackhouse TL;Pike MM;Zhang W;Mishra A
神经血管偶联，即神经元活动在局部血液供应中迅速增加的过程，在中风患者的梗塞以外的脑区域中受损。这种损伤可能会导致神经功能随着时间的推移而恶化，但其机制尚不清楚。使用大脑中动脉闭塞（MCAO）中风模型，我们发现，神经元活动诱发的毛细血管扩张减少了约75%，在梗死边界外的完整皮质组织。这种毛细血管反应性的降低不能用局部神经元活动的减少或血管收缩性的丧失来解释。抑制血管收缩分子20-羟基二十碳四烯酸（20-HETE）的合成，通过抑制其合成酶CYP 450 ω-羟化酶或通过增加一氧化氮（NO），这是ω-羟化酶的天然抑制剂，挽救活动诱发的毛细血管扩张。通过抑制20-HETE暴露的毛细血管扩张依赖于PGE 2激活内过氧化物4（EP 4）受体，这是一种先前在健康动物中发现的血管扩张途径。皮质20-HETE水平增加后MCAO，从中风患者的数据一致。抑制ω-羟化酶使体内20-HETE水平正常化，并增加梗死周围皮质的脑血流量。这些数据确定20-HETE依赖性血管收缩作为中风后毛细血管神经血管耦联损伤的潜在机制。我们的研究结果表明，脑的能量供应可能会显着减少中风后，在以前被认为是无症状的区域，ω-羟化酶抑制剂可能会恢复健康的神经血管耦合中风后。
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.
登录
查看更多内容
影响因子：
12.7
作者：
Korte N;Nortley R;Attwell D
通讯作者：
Attwell D
DOI：
10.1016/bs.apha.2015.05.002
发表时间：
2015
期刊：
Advances in pharmacology (San Diego, Calif.)
影响因子：
--
作者：
Johnson AL;Edson KZ;Totah RA;Rettie AE
通讯作者：
Rettie AE
影响因子：
16.6
作者：
Iturria-Medina Y;Sotero RC;Toussaint PJ;Mateos-Pérez JM;Evans AC;Alzheimer’s Disease Neuroimaging Initiative
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
影响因子：
8.3
作者：
AlonsoGalicia, M;Drummond, HA;Roman, RJ
通讯作者：
Roman, RJ
周细胞变性导致神经血管解偶联并限制大脑的供氧
影响因子：
25
作者：
Kisler K;Nelson AR;Rege SV;Ramanathan A;Wang Y;Ahuja A;Lazic D;Tsai PS;Zhao Z;Zhou Y;Boas DA;Sakadžić S;Zlokovic BV
通讯作者：
Zlokovic BV