The neurovascular unit, matrix proteases, and innate inflammation

Abstract

In the central nervous system, microvessel-neuron interactions appear highly coordinated. The rapid simultaneous responses of the microvasculature, neurons, and glia to focal ischemia in experimental ischemic stroke suggest that these responses could be viewed in a unitary fashion, rather than as individual components. The "neurovascular unit" consists of microvessels (endothelial cells-basal lamina matrix-astrocyte end-feet [and pericytes]), astrocytes, neurons and their axons, and other supporting cells that are likely to modulate the function of the "unit." Each cell component generates an inflammatory response to ischemia. Matrix metalloproteinase (MMP)-9 was first associated with hemorrhagic transformation following focal ischemia in an experimental model. A series of studies of ischemic stroke patients also suggests a relationship between MMP-9 levels and several consequences of ischemic injury, including hemorrhagic transformation. Recent experimental work suggests specific cell sources for MMP-9 generation and for matrix proteases from four distinct families that could impact neurovascular unit integrity.

Figure 1

Relative tissue contents of pro-MMP-2 and pro-MMP-9 following middle cerebral artery occlusion (MCA:O) in the nonhuman primate striatum and their association with hemorrhagic transformation in situ. Significantly increased pro-MMP-9 production is seen in samples with hemorrhage (solid bars), but not in samples without hemorrhage (hatched bars). No correlation was observed for pro-MMP-2 (n = 27 subjects).

Figure 2

Generation of gelatinase activities and related matrix proteases following middle cerebral artery (MCA) occlusion. Proteases and ligands in black have been documented in the striatum of the nonhuman primate following MCA occlusion, while those in gray have not been directly observed or do not change in content (e.g., t-PA). pro-MMP-2 and pro-MMP-9 represent the latent inactive forms observed. Those proteases in boxes have been quantified. The ligands (black) are associated with the cerebral microvasculature. MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; u-PA, urokinase plasminogen activator; t-PA, tissue-type plasminogen activator; MBP, myelin basic protein.^,–