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

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.

Guidelines for the measurement of vascular function and structure in isolated arteries and veins

“…Venules and capillaries are characterized by their thin walls and considerably smaller diameters, respectively (Fig. 14B) (46). The ideal arteriole for cannulating has an opening just at the edge of the slice.…”

Role of Vitamin D Deficiency in the Pathogenesis of Cardiovascular and Cerebrovascular Diseases

“…In order to provide continuous oxygen and nutrient supply for neurons, the cerebral circulation is tightly controlled by myogenic, metabolic, endothelial, and neurovascular mechanisms [ 73 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 ]. VitD also affects many of these critical mechanisms involved in the regulation of cerebral blood flow.…”

A brief overview of a mouse model of cerebral hypoperfusion by bilateral carotid artery stenosis

“…Cerebral blood flow (CBF) after BCAS have been measured by multiple techniques, and in this section, we introduce CBF changes after BCAS operation (Table 3). 12,13,23,24,28–31,33,34,38,48,50,55–57,61,62,64,66,68–89 Laser doppler flowmetry (LDF) and laser speckle imaging (LSI) are the most widely used method for assessing CBF in BCAS mice. The relative CBF of the cortex can be measured by LDF.…”