The “Neuro-Glial-Vascular” Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction

Abstract

The neurovascular unit (NVU) is a complex multi-cellular structure consisting of endothelial cells (ECs), neurons, glia, smooth muscle cells (SMCs), and pericytes. Each component is closely linked to each other, establishing a structural and functional unit, regulating central nervous system (CNS) blood flow and energy metabolism as well as forming the blood-brain barrier (BBB) and inner blood-retina barrier (BRB). As the name suggests, the “neuro” and “vascular” components of the NVU are well recognized and neurovascular coupling is the key function of the NVU. However, the NVU consists of multiple cell types and its functionality goes beyond the resulting neurovascular coupling, with cross-component links of signaling, metabolism, and homeostasis. Within the NVU, glia cells have gained increased attention and it is increasingly clear that they fulfill various multi-level functions in the NVU. Glial dysfunctions were shown to precede neuronal and vascular pathologies suggesting central roles for glia in NVU functionality and pathogenesis of disease. In this review, we take a “glio-centric” view on NVU development and function in the retina and brain, how these change in disease, and how advancing experimental techniques will help us address unanswered questions.

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

“…(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).…”

“…The neurovascular unit (NVU) is a conceptual framework proposed to explain brain functions in health and disease in terms of the interactions between the component cells and the microcirculation in the brain [ 1 , 2 , 3 , 4 , 5 ] ( Figure 1 ). The concept of the NVU was first proposed in 2002 [ 6 ] with the goal of developing innovative treatment strategies for ischemic stroke.…”

“…Since the brain contains neither glucose nor oxygen stores, both glucose and oxygen must be transported from outside the brain by the cerebral blood flow (CBF). The CBF is precisely regulated at all levels of brain vessels, from the main arterial trunks to the small arteries as well as capillaries [ 1 , 2 , 3 , 4 , 5 , 7 , 8 ]. The endothelial cells and astrocytes play important roles in the exchange of substances between the blood and neurons, because the end feet of the astrocytes almost completely ensheath the surfaces of the capillaries [ 19 , 20 , 21 ].…”

Systemic Response to Infection Induces Long-Term Cognitive Decline: Neuroinflammation and Oxidative Stress as Therapeutical Targets

“…Several immune or non-immune events could distort extracellular fluid biochemistry, leading to disabled neuronal/synaptic functions, including alterations in barrier physiology with consequent development of pathophysiology (Johanson and Johanson, 2018). Consequently, NVU is abrogated, with dysregulation of neurovascular coupling, neuron death, gliosis, microglia activation, mural cell transmigration, and BBB breakdown, with consequent increased vascular leakage, transcellular transport, immune cell infiltration, and reduction of tight junctions (Kugler et al, 2021;Shaheryar et al, 2021). In addition, dysregulation of endothelial function by activation of endothelin-1 and nitric oxide (produced by eNOS) induces endothelial activation; cellular inflammatory response; blood flow occlusion; and further neuronal damage, ROS production, and cytokine and matrix metalloprotein-2 and 9 release, which digest proteins responsible for maintaining tight junctions between endothelial cells, compromising the BBB integrity (Tasaki et al, 2014;Park et al, 2018).…”

Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

“…By extending their processes and end-feet along blood vessels, perivascular astrocytes also take part to the formation of the blood-brain-barrier (BBB), the anatomic and biochemical barrier facilitating the entry of nutrients and excluding harmful substances into the brain [ 7 , 8 , 9 ]. Perivascular astrocytes not only participate in BBB formation and maintenance but they also coordinate blood flow with neural activity and brain metabolic needs, forming the so-called neurovascular unit (NVU) [ 10 , 11 ]. In addition, within brain parenchyma, astrocytes share their cytoplasm through gap junction coupling creating a functional reticular system called “astrocyte syncytium”.…”