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Review
. 2022 Nov 1;12(11):1761.
doi: 10.3390/life12111761.

Crosstalk between Blood Vessels and Glia during the Central Nervous System Development

Hidenori Tabata  1
Affiliations
Review

Crosstalk between Blood Vessels and Glia during the Central Nervous System Development

Hidenori Tabata. Life (Basel). .

Abstract

The formation of proper blood vessel patterns in the central nervous system (CNS) is crucial to deliver oxygen and nutrient to neurons efficiently. At the same time, neurons must be isolated from the outer blood circulation by a specialized structure, the blood-brain barrier (BBB), to maintain the microenvironment of brain parenchyma for the survival of neurons and proper synaptic transmission. To develop this highly organized structure, glial cells, a major component of the brain, have been reported to play essential roles. In this review, the crosstalk between the macroglia, including astrocytes and oligodendrocytes, and endothelial cells during the development of CNS will be discussed. First, the known roles of astrocytes in neuro-vascular unit and its development, and then, the requirements of astrocytes for BBB development and maintenance are shown. Then, various genetic and cellular studies revealing the roles of astrocytes in the growth of blood vessels by providing a scaffold, including laminins and fibronectin, as well as by secreting trophic factors, including vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) are introduced. Finally, the interactions between oligodendrocyte progenitors and blood vessels are overviewed. Although these studies revealed the necessity for proper communication between glia and endothelial cells for CNS development, our knowledge about the detailed cellular and molecular mechanisms for them is still limited. The questions to be clarified in the future are also discussed.

Keywords: astrocyte; blood–brain barrier; oligodendrocyte.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Astrocytes form neurovascular units. (a) Astrocytes connect neurons and blood vessels directly. In the cortical gray matter, astrocytes extend highly branched thin processes, whose tips enclose the pre- and post-synapses of neurons. This structure is called “tripartite synapse” (left). Astrocytes sense neurotransmitters via glutamate receptors, such as mGluR5, which propagate Ca2+ transients in astrocytes. Astrocytes release gliotransmitter, ATP and D-Serine, in response to the Ca2+ transient to regulate the synaptic activity. Astrocytes also extend their end-feet and wrap around blood vessels to form the outer most structure of the BBB (right). The schematic drawing shows cross section of BBB. The compartments of basement membrane are shown. Ca2+ waves travel across the cell body and reach the end-feet, and trigger the release of prostaglandin E2 (PgE2) and epoxyeicosatrienoic acids (EETs). (b) Development of tripartite synapse. Astrocytic process releases SPARC and SPARCL1 to induce dendritic spine formation (synaptogenesis, left), and then Glypican 4/6 and SPARCL1 to maturate synapses from inactive state (silent synapse, middle) to active state (right). Astrocytic processes tightly wrap the synapse to form mature tripartite synapse. The illustrations are created with BioRender.com.
Figure 2
Figure 2
The interaction between astrocytes and blood vessels during retinal development. (a) Schematic illustrating of whole retina flat mounts at P1 (upper) and P14 (lower) in mice. During retinal development, astrocytes migrate into the retina from the optic nerve head and spread peripherally along the axons of retinal ganglion cells (RGCs), and then blood vessels grow on the astrocytes. The blue and red lines in upper panel indicate the area covered by astrocytes and blood vessels, respectively. (b) Crosstalk between RGCs, astrocytes, and blood vessels during the retinal development. RGCs express PDGF-A to attract astrocytes. Astrocytes secrete FN, TGF-β and VEGF to regulate angiogenesis, while endothelial cells secrete Ang1 (middle), which upregulates expression of FN from astrocytes (bottom). The thick blue and red arrows indicate the moving and growing directions of astrocytes and blood vessels, respectively. The receptors and ligands involved in migration/extension of astrocytes and blood vessels are shown in (upper) and (lower) panels. The illustrations are created with BioRender.com.
Figure 3
Figure 3
Blood vessel formation and its relationship with radial glia and astrocytes in the cerebral cortex. The blood vessels enter the brain parenchyma from pial and basal plexuses at E10 (left). Primitive blood vessel pattern is formed during the embryonic period (E12-17, middle). E15 onward, astrocytogenesis starts. From the late prenatal stages to the first postnatal week (E17-P7, right), the blood vessels undergoes remodeling. During this period, astrocytes are actively generated and migrate toward brain surface, there they associate with blood vessels, while the radial glia is decreased. The molecules involved in the angiogenesis are shown in a circle window. The initial steps of vascularization are conducted by radial glia. On the other hand, there is a possibility that the remodeling of blood vessels in the later stages is accomplished by astrocytes. The illustrations are created with BioRender.com.
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