Abstract
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.
Highlights
Carotid artery stenosis compromises cerebral blood flow (CBF), giving rise to chronic hypoperfusion and, over time, cognitive decline
Based on our previous findings that myogenic constriction activates TRPV4 ion channels in astrocyte endfeet [12], and that adenosine 1 receptors (A1Rs) activation contributes to arteriole tone, we propose that diminished myogenic responses in bilateral common carotid artery stenosis (BCAS) reduced biomechanically activated endfeet TRPV4 channels and, reduced adenosine availability at the gliovascular interface (Fig. 8)
We demonstrated that BCAS induces a progressive decrease in parenchymal arteriolar tone and reactivity to adenosine
Summary
Carotid artery stenosis compromises cerebral blood flow (CBF), giving rise to chronic hypoperfusion and, over time, cognitive decline. Chronic hypoperfusion is observed in multiple central nervous system diseases, including multiple sclerosis [1, 2], Parkinson’s [3] and Alzheimer’s diseases [4], and vascular dementia [5], and is a consequence of aging [6, 7]. Chronic hypoperfusion may trigger activation of neuroprotective or adaptive processes that serve to compensate for the initial disturbance (i.e., ischemia) With time, these pathways may desensitize or become aberrant, causing the transition to a maladaptive state in which dysfunction and pathological symptoms prevail
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