Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Pharmacology, Larner College of Medicine University of Vermont, Burlington, VT, USA; Institute of Psychiatry and Neurosciences of Paris, INSERM UMR1266, University of Paris, GHU Paris Psychiatrie et Neurosciences, France.
Mech Ageing Dev. 2020 Dec;192:111389. doi: 10.1016/j.mad.2020.111389. Epub 2020 Oct 27.
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 (K1) channel blocker 4-aminopyridine, or by application of heparin-binding EGF-like growth factor (HB-EGF), which promotes K1 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病因，它严重影响了海马体依赖的功能。然而，尽管越来越多的文献涵盖了复杂的神经元相互作用，但对于维持海马微循环的机制却知之甚少。在这里，我们研究了 CADASIL 遗传小鼠模型中海马体小动脉对生理压力的血管收缩反应，这是小动脉的一个基本特征。CADASIL 是一种典型的脑小血管疾病。我们通过对分离的小动脉进行直径和膜电位记录，观察到 CADASIL 中小动脉的压力诱导血管收缩和平滑肌细胞去极化均受损。这种损伤在电压门控钾（K1）通道阻滞剂 4-氨基吡啶存在下或应用肝素结合表皮生长因子样生长因子（HB-EGF）时被消除，后者促进 K1 通道下调。有趣的是，我们观察到 HB-EGF 在 CADASIL 中的小动脉壁内引起心肌细胞膜去极化，但在野生型小动脉中则没有。总之，我们的结果表明，CADASIL 小鼠的海马体小动脉对管腔压力的收缩反应减弱，与我们之前在皮质小动脉和软脑膜动脉中报道的缺陷相似，而 HB-EGF 可挽救这种缺陷。因此，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。
