PIP 通过挽救毛细血管 Kir2.1 的活性来纠正小血管疾病中的脑血流不足。
PIP corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity.
机构信息
Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405;
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
出版信息
Proc Natl Acad Sci U S A. 2021 Apr 27;118(17). doi: 10.1073/pnas.2025998118.
Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis. The capillary endothelial cell strong inward-rectifier K channel Kir2.1, which senses neuronal activity and initiates a propagating electrical signal that dilates upstream arterioles, is a cornerstone of functional hyperemia. Here, using a genetic SVD mouse model, we show that impaired functional hyperemia is caused by diminished Kir2.1 channel activity. We link Kir2.1 deactivation to depletion of phosphatidylinositol 4,5-bisphosphate (PIP), a membrane phospholipid essential for Kir2.1 activity. Systemic injection of soluble PIP rapidly restored functional hyperemia in SVD mice, suggesting a possible strategy for rescuing functional hyperemia in brain disorders in which blood flow is disturbed.
脑小血管疾病（SVD）是中风和痴呆这两种无特定治疗方法的共病之间的一个核心环节。尽管人们越来越认为 SVD 始于血管内皮，但早期的机制在很大程度上仍然未知。向活跃的大脑区域按需输送血液（功能性充血）的能力不足是潜在发病机制的早期表现。毛细血管内皮细胞中的内向整流钾通道 Kir2.1 可以感知神经元活动，并引发扩张上游小动脉的传播性电信号，是功能性充血的基石。在这里，我们使用一种遗传 SVD 小鼠模型表明，功能性充血受损是由于 Kir2.1 通道活性降低所致。我们将 Kir2.1 的失活与磷脂酰肌醇 4,5-二磷酸（PIP）的耗竭联系起来，PIP 是一种对 Kir2.1 活性至关重要的膜磷脂。全身性注射可溶性 PIP 可迅速恢复 SVD 小鼠的功能性充血，这为在血流紊乱的脑疾病中恢复功能性充血提供了一种可能的策略。
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