Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit

Abstract

The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the neurons, astrocytes (astroglia), microvessels, pericytes, and microglia. In addition, we believe that oligodendrocytes should also be included as an indispensable component of the NVU in the white matter. Of all these components, astrocytes in particular have attracted the interest of researchers because of their unique anatomical location; these cells are interposed between the neurons and the microvessels of the brain. Their location suggests that astrocytes might regulate the cerebral blood flow (CBF) in response to neuronal activity, so as to ensure an adequate supply of glucose and oxygen to meet the metabolic demands of the neurons. In fact, the adult human brain, which accounts for only 2% of the entire body weight, consumes approximately 20-25% of the total amount of glucose and oxygen consumed by the whole body. The brain needs a continuous supply of these essential energy sources through the CBF, because there are practically no stores of glucose or oxygen in the brain; both acute and chronic cessation of CBF can adversely affect brain functions. In addition, another important putative function of the NVU is the elimination of heat and waste materials produced by neuronal activity. Recent evidence suggests that astrocytes play pivotal roles not only in supplying glucose, but also fatty acids and amino acids to neurons. Loss of astrocytic support can be expected to lead to malfunction of the NVU as a whole, which underlies numerous neurological disorders. In this review, we shall focus on historical and recent findings with regard to the metabolic contributions of astrocytes in the NVU.

Keywords: astrocyte; astrocyte-neuron lactate shuttle; astroglia; functional hyperemia; glucose; lactate.

Figure 1

Color illustration depicting the “NVU” in both gray and white matter of the human brain. In white matter, both astrocytes and oligodendrocytes are involved in the NVU, since a major part of the neuronal axon is myelinated by oligodendrocytes. Importantly, however, astrocytes can contact axons directly at the site of the Ranvier node. Note that it has not been reported that oligodendrocytes have direct contact with microvessels, since astrocytic endfeet cover microvessels almost completely. Therefore, astrocytes contact oligodendrocytes as well as axons. One of the important roles of astrocyte is the regulation of synaptic transmission. The endfeet of astrocytes envelope synapses (i.e., tripartite synapse). Moreover, astrocytes connect themselves with connexin gap junctions, forming a huge syncytium. At present, the anatomical location of microglia in the NVU is not specified.

Figure 2

The astrocyte-neuron lactate shuttle (ANLS) model. Glucose is supplied from within the brain capillaries to neurons and astrocytes. For neurons, in addition to the direct supply shown by the dotted line, glucose-derived lactate metabolized in astrocytes may be supplied to neurons as an energy substrate. Importantly, lactate derived from either glucose or glutamate in astrocytes can act as vasodilatory signal on capillaries in the brain. (adapted from [20]). ① Na⁺,K⁺-ATPase ② Glucose transporter 1 (Glut1) ③ Glucose transporter 3 (Glut3) ④ Monocarboxylic acid transporter (MCT) 1&4 astrocytic form ⑤ Monocarboxylic acid transporter (MCT) 2 (neuronal form) ⑥ System N transporter (astrocytic form) ⑦ System A transporter (neuronal form) ⑧ Na⁺-dependent glutamate transporter (GLT1, GLAST).