Rosehart Amanda C, Longden Thomas A, Weir Nick, Fontaine Jackson T, Joutel Anne, Dabertrand Fabrice
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Department of Physiology, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, United States.
Front Aging Neurosci. 2021 Aug 13;13:695965. doi: 10.3389/fnagi.2021.695965. eCollection 2021.
Prostaglandin E (PGE) has been widely proposed to mediate neurovascular coupling by dilating brain parenchymal arterioles through activation of prostanoid EP4 receptors. However, our previous report that direct application of PGE induces an EP1-mediated constriction strongly argues against its direct action on arterioles during neurovascular coupling, the mechanisms sustaining functional hyperemia. Recent advances have highlighted the role of capillaries in sensing neuronal activity and propagating vasodilatory signals to the upstream penetrating parenchymal arteriole. Here, we examined the effect of capillary stimulation with PGE on upstream arteriolar diameter using an capillary-parenchymal arteriole preparation and cerebral blood flow measurements with two-photon laser-scanning microscopy. We found that PGE caused upstream arteriolar dilation when applied onto capillaries with an EC of 70 nM. The response was inhibited by EP1 receptor antagonist and was greatly reduced, but not abolished, by blocking the strong inward-rectifier K channel. We further observed a blunted dilatory response to capillary stimulation with PGE in a genetic mouse model of cerebral small vessel disease with impaired functional hyperemia. This evidence casts previous findings in a different light, indicating that capillaries are the locus of PGE action to induce upstream arteriolar dilation in the control of brain blood flow, thereby providing a paradigm-shifting view that nonetheless remains coherent with the broad contours of a substantial body of existing literature.
前列腺素E（PGE）已被广泛认为可通过激活前列腺素EP4受体使脑实质小动脉扩张来介导神经血管耦合。然而，我们之前的报告指出，直接应用PGE会诱导EP1介导的收缩，这有力地反驳了其在神经血管耦合（即维持功能性充血的机制）过程中对小动脉的直接作用。最近的进展突出了毛细血管在感知神经元活动以及将血管舒张信号传递至上游穿通实质小动脉方面的作用。在此，我们使用毛细血管 - 实质小动脉标本以及双光子激光扫描显微镜测量脑血流量，研究了用PGE刺激毛细血管对上游小动脉直径的影响。我们发现，当以70 nM的有效浓度将PGE应用于毛细血管时，会引起上游小动脉扩张。该反应被EP1受体拮抗剂抑制，并且通过阻断强内向整流钾通道可使其大幅降低，但并未消除。我们进一步观察到，在功能性充血受损的脑小血管病基因小鼠模型中，对PGE刺激毛细血管的扩张反应减弱。这一证据使之前的研究结果有了不同的解读，表明毛细血管是PGE在控制脑血流量过程中诱导上游小动脉扩张的作用位点，从而提供了一种范式转变的观点，不过这一观点与大量现有文献的大致轮廓仍保持一致。
