The neurovascular unit in the setting of stroke

Abstract

Microvessels and neurons respond rapidly and simultaneously in focal regions of ischaemic injury in such a way as to suggest that the responses could be coordinated. The ability of neurons to modulate cerebral blood flow in regions of activation results from neurovascular coupling. But little is known about the microvessel-to-neuron direction of the relationship. The presence and participation of intervening glial cells implies the association of microvessels, glia, and neurons in a 'neurovascular unit'. The interdependent functions of the cellular and matrix components of this theoretical unit have not been rigorously explored, except under conditions of injury where, for the most part, only single components or tissue samples have been studied. Whereas maintenance or timely re-establishment of flow reduces tissue and neuron injury in both humans and animal models, protection of neuron function in humans has not prevented the evolution of injury despite the inherent mechanisms of neurovascular coupling. However, occlusion of flow to the brain rapidly identifies regions of neuron-vascular vulnerability within the vascular territory-at-risk. These coalesce to become the mature ischaemic lesion. The failure, so far, of clinical trials of neuron protectant agents to achieve detectable tissue salvage could be explained by the vulnerability (and lack of protection) of essential components of the 'unit'. This presentation summarizes evidence and thoughts on this topic. These support the need to understand component interactions within the neurovascular unit.

Fig. 1

A schematic of the ‘neurovascular unit’. Denoting the inter-relationship of microvessels to their dependent neurons and axons, via astrocytes. Injury to any component is likely to affect the function of the entire unit.

Fig. 2

The effects of focal ischaemia on the neurovascular unit. (a) The distance between microvessels and neurons [(m–n) distance] within the striatum of the nonhuman primate (Papio anubis/cynocephalus) as a measure of neurovascular integrity. (b) Injured neurons (n*), uninjured neurons (n), and microvessels (m) scattered within the ischaemic core at 2 h following middle cerebral artery (MCA) occlusion in the nonhuman primate. (c) (m–n) Distance distribution based upon measurements of normoxic striatal neurons and their proximate microvessels. (d) Demonstration that neurons more distant from their nearest microvessel [(m–n*)] are significantly more likely to display injury than those at lesser distance [(m–n)] in the ischaemic striatum at 2 h post-MCA occlusion [24].

Fig. 3

Impact of ischaemia on the expression of matrix integrin receptors by microvessel endothelium, and matrix integrins and dystroglycan receptors on astrocyte end-feet in a model cerebral capillary. All changes occur within 2 h of MCA occlusion in the nonhuman primate striatum.