Capillaries as a Sensory Web that Controls Cerebral Blood Flow in Health and Disease

项目总结 大脑中的神经元具有有限的能量储备，因此依赖于“及时”传递策略，在这种策略中 活跃的神经元向脑微血管系统发出信号，以增加局部脑血流量(CBF)，重新供应 营养和氧气，以及去除有毒的代谢物。尽管进行了广泛的研究，但这些机制 神经代谢需求和血管供应之间的功能联系，称为 神经血管偶联(NVC)，目前仍知之甚少。流向大脑的血液是由脑实质调节的。 小动脉和数百英里长的毛细血管，这极大地扩展了灌注的范围。我们最近 提出了支持大脑毛细血管作为神经元活动感知网络的概念的证据， 证明脑毛细血管内皮细胞(CECs)能够启动电刺激 (超极化)对上游传播的神经元活动作出反应而导致摄食扩张的信号 并在信号起始处增加局部血流量。我们已经建立了机械论 这一电信号的基础，表明神经元和/或星形胶质细胞来源的钾(K+)是关键 并确定强内向整流性K+通道Kir2.1为关键分子。我们有 最近发现了基于钙信号的第二种基本NVC机制， 不同的动力学和调节特征，也在大脑毛细血管中起作用，并可以由假定的 NVC介体前列腺素E2(PGE2)。我们进一步发现了Gq蛋白启动的一种机制 偶联受体信号转导与膜磷脂酰肌醇4，5-二磷酸的动态变化 二磷酸(PIP2)水平控制着电信号和钙信号之间的平衡。额外的初步报告 2+ 数据支持通过钙离子依赖的内皮一氧化氮信号转导和周细胞- 调节NVC时对毛细血管血流的中介调节。这项提议的近期目标是 在分子上创建电子、钙离子和相关调控信号机制的综合视图， 生物物理和计算建模水平，通过检查它们在日益复杂的细分市场中的操作 在体外、体内和硅胶中的脑血管系统。最终，我们建议编织这些研究线索 共同创建大脑中生理毛细血管到小动脉/软脑膜动脉信号的系统级视图， 并测试这种感官网络的逐渐退化和随之而来的逐渐衰退的概念 脑血管功能是导致脑部小血管疾病的重要因素。

PROJECT SUMMARY Neurons in the brain have limited energy reserves and thus rely on a “just-in-time” delivery strategy in which active neurons signal to the brain microvasculature to increase regional cerebral blood flow (CBF), resupplying nutrients and oxygen as well as removing toxic metabolites. Despite extensive study, the mechanisms underlying the functional linkage between neuronal metabolic demand and vascular supply, termed neurovascular coupling (NVC), remain poorly understood. Blood flow to the brain is mediated by parenchymal arterioles and hundreds of miles of capillaries, which enormously extend the territory of perfusion. We recently presented evidence supporting the concept that brain capillaries act as a neuronal activity-sensing network, demonstrating that brain capillary endothelial cells (cECs) are capable of initiating an electrical (hyperpolarizing) signal in response to neuronal activity that propagates upstream to cause dilation of feeding arterioles and increase blood flow locally at the site of signal initiation. We have established the mechanistic basis for this electrical signal, showing that neuron- and/or astrocyte-derived potassium (K+) is the critical mediator and identifying the strong inward rectifier K+ channel, Kir2.1, as the key molecular player. We have recently discovered that a second fundamental NVC mechanism based on calcium (Ca2+) signaling, with distinct kinetics and regulatory features, also operates in brain capillaries, and can be initiated by the putative NVC mediator prostaglandin E2 (PGE2). We have further found that a mechanism initiated by Gq-protein coupled receptor signaling and mediated by dynamic changes in membrane phosphatidylinositol 4,5- bisphosphate (PIP2) levels controls the balance between electrical and Ca signaling. Additional preliminary 2+ data support a role for gasotransmission via Ca2+-dependent endothelial nitric oxide signaling and pericyte- mediated regulation of capillary blood flow in modulating NVC. The immediate goals of this proposal are to create an integrated view of electrical, Ca2+ and related regulatory signaling mechanisms at molecular, biophysical, and computational-modeling levels by examining their operation in increasingly complex segments of the brain vasculature ex vivo, in vivo, and in silico. Ultimately, we propose to weave these research threads together to create a systems-level view of physiological capillary-to-arteriole/pial artery signaling in the brain, and test the concept that gradual degradation of this sensory web and the attendant progressive decay of cerebrovascular function contributes to small vessel diseases of the brain.