Decreased parenchymal arteriolar tone uncouples vessel-to-neuronal communication in a mouse model of vascular cognitive impairment.

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.

Vasculo-Neuronal Coupling and Neurovascular Coupling at the Neurovascular Unit: Impact of Hypertension.

Components of the neurovascular unit (NVU) establish dynamic crosstalk that regulates cerebral blood flow and maintain brain homeostasis. Here, we describe accumulating evidence for cellular elements of the NVU contributing to critical physiological processes such as cerebral autoregulation, neurovascular coupling, and vasculo-neuronal coupling. We discuss how alterations in the cellular mechanisms governing NVU homeostasis can lead to pathological changes in which vascular endothelial and smooth muscle cell, pericyte and astrocyte function may play a key role. Because hypertension is a modifiable risk factor for stroke and accelerated cognitive decline in aging, we focus on hypertension-associated changes on cerebral arteriole function and structure, and the molecular mechanisms through which these may contribute to cognitive decline. We gather recent emerging evidence concerning cognitive loss in hypertension and the link with vascular dementia and Alzheimer's disease. Collectively, we summarize how vascular dysfunction, chronic hypoperfusion, oxidative stress, and inflammatory processes can uncouple communication at the NVU impairing cerebral perfusion and contributing to neurodegeneration.