Thakore Pratish, Yamasaki Evan, Ali Sher, Solano Alfredo Sanchez, Labelle-Dumais Cassandre, Gao Xiao, Chaumeil Myriam M, Gould Douglas B, Earley Scott
bioRxiv. 2023 Mar 6:2023.03.03.531032. doi: 10.1101/2023.03.03.531032.
Neurovascular coupling (NVC), a vital physiological process that rapidly and precisely directs localized blood flow to the most active regions of the brain, is accomplished in part by the vast network of cerebral capillaries acting as a sensory web capable of detecting increases in neuronal activity and orchestrating the dilation of upstream parenchymal arterioles. Here, we report a mutant mouse model of cerebral small vessel disease (cSVD) with age-dependent defects in capillary-to-arteriole dilation, functional hyperemia in the brain, and memory. The fundamental defect in aged mutant animals was the depletion of the minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP ) in brain capillary endothelial cells, leading to the loss of inwardly rectifier K (Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K), an enzyme that diminishes the bioavailability of PIP by converting it to phosphatidylinositol (3,4,5)-trisphosphate (PIP ), restored Kir2.1 channel activity, capillary-to-arteriole dilation, and functional hyperemia. In longitudinal studies, chronic PI3K inhibition also improved the memory function of aged mutant mice. Our data suggest that PI3K inhibition is a viable therapeutic strategy for treating defective NVC and cognitive impairment associated with cSVD.
ONE-SENTENCE SUMMARY: PI3K inhibition rescues neurovascular coupling defects in cerebral small vessel disease.
神经血管耦合（NVC）是一种重要的生理过程，可快速、精确地将局部血流导向大脑最活跃的区域，部分是通过庞大的脑毛细血管网络实现的，这些毛细血管充当一个感觉网络，能够检测神经元活动的增加并协调上游实质小动脉的扩张。在此，我们报告了一种脑小血管疾病（cSVD）的突变小鼠模型，该模型在毛细血管到小动脉的扩张、脑功能充血和记忆方面存在年龄依赖性缺陷。老年突变动物的根本缺陷是脑毛细血管内皮细胞中次要膜磷脂磷脂酰肌醇4,5-二磷酸（PIP₂）的消耗，导致内向整流钾（Kir2.1）通道活性丧失。阻断磷脂酰肌醇-3-激酶（PI3K），一种通过将PIP₂转化为磷脂酰肌醇（3,4,5）-三磷酸（PIP₃）来降低PIP₂生物利用度的酶，可恢复Kir2.1通道活性、毛细血管到小动脉的扩张和功能充血。在纵向研究中，慢性PI3K抑制还改善了老年突变小鼠的记忆功能。我们的数据表明，PI3K抑制是治疗与cSVD相关的NVC缺陷和认知障碍的一种可行治疗策略。
PI3K抑制可挽救脑小血管疾病中的神经血管耦合缺陷。
