Microglia have a grip on brain microvasculature

Abstract

Microglia are brain resident immune cells with multiple functions. However, little is known about microglia-vascular interactions. In a recent paper published in Nature Communications, Bisht et al. identify a signalling mechanism that attracts and maintains microglia at the capillary wall. Moreover, they show that microglia regulate capillary vascular tone, playing a more significant role in blood flow regulation than previously thought.Microglia are the resident immune sentinels of the brain, responsible for the brain immune response as well as a variety of physiological functions including synapse pruning, neuronal regulation, and clearance of cellular and toxic debris [1][2][3][4] . However, much less is known about microglia-vascular interactions, particularly under healthy steady-state conditions.Recent studies using live 2-photon imaging, confocal, expansion, super-resolution, and electron microscopy, suggested that microglia associate with capillary vasculature at all ages and during central nervous system development, notably in areas lacking astrocyte endfoot coverage. They also suggested that motility of juxtavascular microglia declined as astrocyte endfeet more fully ensheathed the vasculature 2 . Others have suggested that during developmental colonization of the retina, microglia migrate to contact the deep nuclear retinal layer of high stiffness, which coincides with microglia bipolarization, reduction in transforming growth factor-β1 signaling and termination of vascular growth 3 . Yet in the adult brain, microglia are an often overlooked component of the neurovascular unit (NVU) -a basic functional unit of the brain coordinating neuronal functions with vascular functions.The NVU is composed of a collection of functionally interacting cells that form, maintain, and regulate brain vasculature including blood-brain barrier (BBB) integrity and cerebral blood flow (CBF) regulation. This includes endothelial cells, mural cells (pericyte, smooth muscle), glia (microglia, astrocytes, oligodendrocytes), and neurons 5 . Among these cell types, endothelial cells make up a continuous tightly junctioned inner monolayer of the vessel walls forming the BBB, which is surrounded by a basement membrane and other cells of the NVU, as illustrated here at the level of brain capillary (Fig. 1). At the capillary level, pericytes play an essential role in maintaining BBB integrity [5][6][7] . Interestingly, recent work suggested that microglia could also play a role in repairing damaged BBB 1,8 . One study suggested that microglia migrate rapidly to the site of laser-induced focal capillary wall lesions to seal and repair the damaged BBB, which required G-protein coupled purinergic receptor P2RY12 on microglia 8 . Similar microglia migration to the BBB was observed in the Murphy Roths Large/lymphoproliferation (MRL/lpr) mouse model of systemic lupus erythematosus, which also exhibits BBB breakdown 1 .

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction

“…However, their role in bAVM pathology is not yet clear. The capillary-associated microglia interact closely with the ECs, astrocytes, and pericytes that comprise the brain's microvascular unit and blood-brain barrier (BBB) [58][59][60]. In a pathologic condition such as bAVM, damaged ECs can be the source of sENG [9].…”

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

“…Capillary-associated microglia also contribute to blood flow regulation since they are involved in regulating capillary vascular tone ( Bisht et al, 2021 ; Kisler et al, 2021 ). Furthermore, similar to astrocytes, microglia contribute to the glia limitans (glial end-feet layer) forming the BBB around capillaries, and can structurally remodel the vasculature through the phagocytosis of endothelial cells ( Haruwaka et al, 2019 ).…”

Targetability of the neurovascular unit in inflammatory diseases of the central nervous system

“…Recently, Kisler et al used two-photon in vivo imaging to observe microglial processes covering many of these gaps. 29 How involved microglia are in the structure of the NVU is still being investigated. By area, neurons have a relatively minor role in the structure of the NVU but can modulate BBB permeability via neuronal activity.…”

“…130 Although it has been long appreciated that microglia is vital to the health of the CNS, surveying along the BBB and responding quickly to breaches, they are a relatively recent addition to the NVU and provide coverage of BBB areas not wrapped by astrocytes. 29,131 In addition, microglia are known to signal to other members of the NVU and communicate with peripheral immune cells, 6 attracting and/or activating them within the CNS parenchyma during injury and infection as sentinels of the CNS. [132][133][134][135] Activated microglia and peripheral immune cells can secrete a number of factors that modulate BBB integrity (Figure 2).…”