Vascular cognitive impairment, the second most common cause of dementia, profoundly affects hippocampal-dependent functions. However, while the growing literature covers complex neuronal interactions, little is known about the sustaining hippocampal microcirculation. Here we examined vasoconstriction to physiological pressures of hippocampal arterioles, a fundamental feature of small arteries, in a genetic mouse model of CADASIL, an archetypal cerebral small vessel disease. Using diameter and membrane potential recordings on isolated arterioles, we observed both blunted pressure-induced vasoconstriction and smooth muscle cell depolarization in CADASIL. This impairment was abolished in the presence of voltage-gated potassium (K_V1) channel blocker 4-aminopyridine, or by application of heparin-binding EGF-like growth factor (HB-EGF), which promotes K_V1 channel down-regulations. Interestingly, we observed that HB-EGF induced a depolarization of the myocyte plasma membrane within the arteriolar wall in CADASIL, but not wild-type, arterioles. Collectively, our results indicate that hippocampal arterioles in CADASIL mice display a blunted contractile response to luminal pressure, similar to the defect we previously reported in cortical arterioles and pial arteries, that is rescued by HB-EGF. Hippocampal vascular dysfunction in CADASIL could then contribute to the decreased vascular reserve associated with decreased cognitive performance, and its correction may provide a therapeutic option for treating vascular cognitive impairment.

血管性认知障碍是痴呆症的第二大常见原因，深刻影响海马依赖性功能。然而，虽然越来越多的文献涵盖了复杂的神经元相互作用，但对维持海马微循环知之甚少。在这里，我们在 CADASIL（一种典型的脑小血管疾病）的遗传小鼠模型中检查了血管收缩对海马小动脉生理压力的影响，这是小动脉的一个基本特征。使用孤立小动脉的直径和膜电位记录，我们在 CADASIL 中观察到钝性压力诱导的血管收缩和平滑肌细胞去极化。在电压门控钾 (K _V1) 通道阻滞剂 4-氨基吡啶，或通过应用肝素结合 EGF 样生长因子 (HB-EGF)，促进 K _V 1 通道下调。有趣的是，我们观察到 HB-EGF 诱导 CADASIL 小动脉壁内肌细胞质膜的去极化，而不是野生型小动脉。总的来说，我们的结果表明，CADASIL 小鼠的海马小动脉对管腔压力表现出迟钝的收缩反应，类似于我们之前在皮质小动脉和软脑膜动脉中报告的缺陷，由 HB-EGF 挽救。CADASIL 中的海马血管功能障碍可能导致与认知能力下降相关的血管储备减少，其纠正可能为治疗血管性认知障碍提供一种治疗选择。