Chronic hypoperfusion is a key contributor to cognitive decline and neurodegenerative conditions, but the cellular mechanisms remain ill-defined. Using a multidisciplinary approach, we sought to elucidate chronic hypoperfusion-evoked functional changes at the neurovascular unit. We used bilateral common carotid artery stenosis (BCAS), a well-established model of vascular cognitive impairment, combined with an ex vivo preparation that allows pressurization of parenchymal arterioles in a brain slice. Our results demonstrate that mild (~ 30%), chronic hypoperfusion significantly altered the functional integrity of the cortical neurovascular unit. Although pial cerebral perfusion recovered over time, parenchymal arterioles progressively lost tone, exhibiting significant reductions by day 28 post-surgery. We provide supportive evidence for reduced adenosine 1 receptor-mediated vasoconstriction as a potential mechanism in the adaptive response underlying the reduced baseline tone in parenchymal arterioles. In addition, we show that in response to the neuromodulator adenosine, the action potential frequency of cortical pyramidal neurons was significantly reduced in all groups. However, a significant decrease in adenosine-induced hyperpolarization was observed in BCAS 14 days. At the microvascular level, constriction-induced inhibition of pyramidal neurons was significantly compromised in BCAS mice. Collectively, these results suggest that BCAS uncouples vessel-to-neuron communication—vasculo-neuronal coupling—a potential early event in cognitive decline.

慢性灌注不足是认知能力下降和神经退行性疾病的一个关键因素，但其细胞机制仍不明确。我们采用多学科方法，试图阐明神经血管单元慢性灌注不足引起的功能变化。我们使用双侧颈总动脉狭窄（BCAS），这是一种成熟的血管认知障碍模型，并结合离体制剂，可以对脑切片中的实质小动脉加压。我们的结果表明，轻度（约 30%）、慢性灌注不足显着改变了皮质神经血管单元的功能完整性。尽管软脑膜脑灌注随着时间的推移而恢复，但实质小动脉逐渐失去张力，到术后第 28 天表现出显着减少。我们提供了支持性证据，证明腺苷 1 受体介导的血管收缩减少是实质小动脉基线张力降低的适应性反应的潜在机制。此外，我们发现，在神经调节剂腺苷的作用下，所有组中皮质锥体神经元的动作电位频率均显着降低。然而，在 BCAS 14 天中观察到腺苷诱导的超极化显着降低。在微血管水平上，BCAS 小鼠中收缩诱导的锥体神经元抑制显着受损。总的来说，这些结果表明 BCAS 解开了血管与神经元的通讯（血管-神经元耦合），这是认知能力下降的潜在早期事件。