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.

Keywords: Müller glia; astrocytes; brain; neurovascular unit; retina.

FIGURE 1

Schematic of the neurovascular unit (NVU) in health and disease. The NVU is a hetero-cellular complex formed by glia, neurons, vSMCs, pericytes, microglia, and blood vessels, that form the blood-brain barrier (BBB) and blood retina barrier (BRB). Glia cells (green) impact neurons (orange), endothelial cells (ECs) (magenta), and each other. For NVU functionality, various direct (i.e., glia-to-glia, tripartite synapse, endfoot-to-EC, EC-to-endfoot) and indirect (i.e., neuron-to-EC via glia, neuron-to-EC via mural cells, microglia) pathways need to be considered. Upon disease multi-level changes are observed, including altered cell shapes, function, and interactions [see also (Lécuyer et al., 2016; Jha et al., 2018)]. NVU component changes include gliosis, neuron death, EC-connectivity changes, mural cell transmigration, and microglia activation.

FIGURE 2

Glia-endothelial interactions. (A) Pathways across the BBB and BRB allow for the transport of various types of molecules. (B) Glial signaling impacts ECs [i.e., glial-derived neurotrophic factor (GDNF), transforming growth factor β (TGF-β), Ang1, fibroblast growth factor 2 (FGF2), and vascular endothelial growth factor (VEGF)] and in turn BBB stability (dotted arrow). (C) BBB stability is highly dependent on EC inter-cellular junction integrity including adherens junctions, gap junctions, junctional adhesion molecules, and tight junctions adapted from Abbott et al. (2006); Malik and Di Benedetto (2018).

FIGURE 3

Advancements in image acquisition methods and resolution, enable the study of NVU component interactions as shown here by the interaction between MG endfeet (blue) and blood vessels (magenta), separated by the BM (white arrowhead; inset) in the developing zebrafish retina. The image was acquired with Zeiss LSM 900 AiryScan2 microscopy that allows in vivo acquisition with a resolution of 120 × 120 × 350 nm (x,y,z).