Role of neurovascular uncoupling in cognitive decline induced by metabolic disturbances: vascular explorations in a mice model

Introduction

A link between vascular risk factors caused by metabolic disorders in mid-life and the onset of cognitive impairments has been evidenced. Our team has demonstrated that, in a mice model, a cognitive decline occurred after 6 months of high-fat diet (HFD). The cognitive impairment onset was concomitant to that of metabolic disorders and a dysfunction in cerebrovascular relaxation in regions involved in the altered cognitive tasks. This could be caused by a neurovascular coupling dysfunction, which allows the adjustment of cerebral blood flow to neuronal activity. Glutamate, both an excitative neurotransmitter and potent vasodilator, could be involved. When released, glutamate can activate a neuronal pathway involving nNOS and COX2 and/or an astrocytic pathway involving COX1. Those enzymes then produce vasodilatory agents. Our aim is to investigate potential neurovascular alterations induced by metabolic disorders by focusing on the role of vasoactive enzymes.

Methods

Male C57Bl6/J mice are fed with HFD or normal diet for 12 months. Vasomotricity of basilar artery and neurovascular coupling assessments are performed with Halpern's arteriograph and with an ex-vivo brain slice model using pharmacological modulation.

Results

Mice fed with HFD demonstrate a significantly decreased myogenic tone of the basilar artery, that is conversely correlated with weight gain. The vasodilatory response to glutamate was decreased in intraparenchymal arterioles of the animals in the HFD group compared to that of the control group. Specific inhibition of the enzymes involved in the glutamatergic pathways may demonstrate a different pattern of involvement of each of these enzymes in the vasodilatory response to glutamate of the HFD-fed mice, pointing to a greater participation of the neuronal pathway enzymes (nNOS and COX2).

Discussion

These results indicate that HFD could modify the basal functioning of cerebral arteries as well as their interaction with neurons and astrocytes, indicating a potential neurovascular uncoupling in our model. The reduced vasodilatory effect of glutamate in HFD-mice seems to be related to a decreased activation of COX1 to the profit of the glutamatergic neuronal pathway, notably of COX 2, whose expression is known to be increased in neuroinflammation, a recurrent occurrence in metabolic syndrome models as ours.