Astrocyte Activation in Neurovascular Damage and Repair Following Ischaemic Stroke

Abstract

Transient or permanent loss of tissue perfusion due to ischaemic stroke can lead to damage to the neurovasculature, and disrupt brain homeostasis, causing long-term motor and cognitive deficits. Despite promising pre-clinical studies, clinically approved neuroprotective therapies are lacking. Most studies have focused on neurons while ignoring the important roles of other cells of the neurovascular unit, such as astrocytes and pericytes. Astrocytes are important for the development and maintenance of the blood-brain barrier, brain homeostasis, structural support, control of cerebral blood flow and secretion of neuroprotective factors. Emerging data suggest that astrocyte activation exerts both beneficial and detrimental effects following ischaemic stroke. Activated astrocytes provide neuroprotection and contribute to neurorestoration, but also secrete inflammatory modulators, leading to aggravation of the ischaemic lesion. Astrocytes are more resistant than other cell types to stroke pathology, and exert a regulative effect in response to ischaemia. These roles of astrocytes following ischaemic stroke remain incompletely understood, though they represent an appealing target for neurovascular protection following stroke. In this review, we summarise the astrocytic contributions to neurovascular damage and repair following ischaemic stroke, and explore mechanisms of neuroprotection that promote revascularisation and neurorestoration, which may be targeted for developing novel therapies for ischaemic stroke.

Keywords: astrocyte; neuroinflammation; neuroprotection; neurorestoration; neurotoxicity; neurovascular; secretion; stroke.

Figure 1

The diverse functions of astrocytes during physiological and pathophysiological conditions. Astrocytes have several important roles in the healthy and diseased brain. They are the main housekeeping cells of the brain, and can exert either protective or detrimental effects on neurons during pathophysiological conditions. Astrocytes are essential for the development and maintenance of the BBB, homeostasis of the brain microenvironment, cerebral blood flow regulation, neurotransmitter uptake, synaptogenesis, neurogenesis and release of neurotrophic factors and energy supply to neurons. Astrocytes also play a major role during pathophysiological conditions. Neuronal survival heavily depends on astrocytes. For example, neurons do not survive if neighbouring astrocytes are lost during an ischaemic stroke. Cerebral ischaemia leads astrocytes to change their morphology and function, causing astrocytes to become reactive, thereby producing several proinflammatory modulators and participating in glial scar formation. Their neuroprotective roles include clearing glutamate from synaptic regions, secretion of neurotrophic factors and promotion of angiogenesis, neurogenesis, synaptogenesis and axonal remodelling. Figure created with BioRender.com.

Figure 2

Blood–brain barrier (BBB) dysfunction following ischaemic stroke. (1) Simplified structure of the neurovascular unit (NVU) comprising brain endothelial cells, astrocytes, pericytes and neurons. Brain endothelial cells form tight junctions between them that control the movement of molecules through the paracellular pathway by showing size and charge selectivity, thereby forming a selective barrier between the brain microenvironment and the systemic circulation. Pericytes partially cover the endothelial cells and are embedded in the basement membrane. They are spread discontinuously along the microvessel, and maintain the barrier properties of brain endothelial cells, regulate capillary diameter, cerebral blood flow and angiogenesis. Perivascular endfeet from multiple astrocytes ensheath endothelial cells, allowing intricate cell–cell communications to help maintain the BBB phenotype of brain endothelial cells. Astrocytes secrete soluble factors that are important for the development and maintenance of the BBB. In addition, astrocytes contribute to brain water homeostasis via aquaporin 4 (AQP4) water channels, which are expressed on the endfeet of astrocytes. (2) The schematic on the right demonstrates BBB dysfunction due to cerebral ischaemia. Loss of tissue perfusion due to ischaemic stroke leads to neuronal injury and death. This causes an increase in the release of proinflammatory mediators that activates endothelial cells, astrocytes and pericytes. The resulting neurovascular inflammation disrupts tight junctions, leading to paracellular leakage and cerebral oedema. During ischaemia, AQP4 lose their polarisation from astrocyte endfeet. A dual role is played by AQP4 in cytotoxic and vasogenic oedema, where AQP4 deficiency leads to a reduction in cytotoxic oedema and improved neurological outcomes, and vasogenic oedema is increased when AQP4 is knocked down. The activated brain endothelium attracts leukocytes, which results in increased transcytosis across the BBB and neuroinflammation. This proinflammatory environment leads to changes in astrocyte morphology: “reactive astrogliosis”. Reactive astrocytes can secrete proinflammatory mediators such as IL-1α, IL-6 and TNF-α that cause further BBB disruption and neuronal injury. In addition, ischaemic stroke causes pericyte detachment and death in rigor, which can lead to vessel constriction and the no-reflow phenomenon. Figure created with BioRender.com.