Isaacs Dominic, Xiang Liuruimin, Hariharan Ashwini, Longden Thomas A
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
Laboratory of Neurovascular Interactions, Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201.
Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2405965121. doi: 10.1073/pnas.2405965121. Epub 2024 Dec 4.
The brain has evolved mechanisms to dynamically modify blood flow, enabling the timely delivery of energy substrates in response to local metabolic demands. Several such neurovascular coupling (NVC) mechanisms have been identified, but the vascular signal transduction and transmission mechanisms that enable dilation of penetrating arterioles (PAs) remote from sites of increased neuronal activity are unclear. Given the exponential relationship between vessel diameter and blood flow, tight control of arteriole membrane potential and diameter is a crucial aspect of NVC. Recent evidence suggests that capillaries play a major role in sensing neural activity and transmitting signals to modify the diameter of upstream vessels. Thin-strand pericyte cell bodies and processes cover around 90% of the capillary bed, and here we show that these cells play a central role in sensing neural activity and generating and relaying electrical signals to arterioles. We identify a K channel-dependent neurovascular signaling pathway that is explained by the recruitment of thin-strand pericytes and we deploy vascular optogenetics to show that currents generated in individual thin-strand pericytes are sent over long distances to upstream arterioles to cause dilations in vivo. Genetic disruption of vascular K channels reduces the arteriole diameter response to neural activity and laser ablation of thin-strand pericytes eliminates the K-dependent component of NVC. Together, our findings indicate that thin-strand pericytes sense neural activity and transform this into K channel-dependent electrometabolic signals that inform upstream arterioles of local energy needs, promoting spatiotemporally precise energy distribution.
大脑已经进化出动态调节血流的机制，能够根据局部代谢需求及时输送能量底物。已经确定了几种这样的神经血管耦合（NVC）机制，但能够使远离神经元活动增加部位的穿通小动脉（PA）扩张的血管信号转导和传递机制尚不清楚。鉴于血管直径与血流之间的指数关系，严格控制小动脉膜电位和直径是NVC的一个关键方面。最近的证据表明，毛细血管在感知神经活动以及将信号传递以改变上游血管直径方面发挥着主要作用。细索状周细胞的细胞体和突起覆盖了约90%的毛细血管床，在这里我们表明这些细胞在感知神经活动以及产生和向小动脉传递电信号方面发挥着核心作用。我们确定了一条依赖钾通道的神经血管信号通路，该通路可通过细索状周细胞的募集来解释，并且我们应用血管光遗传学来表明单个细索状周细胞中产生的电流被远距离发送到上游小动脉，从而在体内引起血管扩张。血管钾通道的基因破坏降低了小动脉直径对神经活动的反应，细索状周细胞的激光消融消除了NVC中依赖钾通道的成分。总之，我们的研究结果表明，细索状周细胞感知神经活动并将其转化为依赖钾通道的电代谢信号，向上游小动脉传达局部能量需求，促进时空精确的能量分布。
