Fig. 1 The neurovascular unit (NVU): a key role of the NVU is to facilitate adjustments of local blood flow and the permeability of capillaries to neuronal activity in a feed-forward manner. An important factor that regulates local blood flow in the brain is the contractility of pericytes; both pericytes and endothelial cells come in close contact with end feet of astrocytes; the latter cells play a key role in neurovascular coupling because they are in close proximity to neuronal synapses (thus, have paracrine signaling from these cells) on one side and have end feet that come in close contact with endothelial cells and pericytes on the other side, which permits paracrine and direct cell-to-cell communication. Microglia survey the microenvironment, though a precise role of these cells on brain capillaries in physiological conditions is not well established yet.

Fig. 2 A simplified diagram of paracrine signaling in the neurovascular unit. Neuronal activity (i.e. glutamate release) induces vasodilation through its action on interneurons or astrocytes. As a response to this stimulation, interneurons release NO (1), while astrocytes induce vasodilation through several mechanisms (2, 3). In addition to that, astrocyte-derived AA (4) could be metabolized into 20-hydroxy-eicosatetraenoic acid (20-HETE) in smooth muscle cells, which then induces vasoconstriction. Signaling from capillaries affects the tone of vascular smooth muscle cells via astrocytes (5). PGE-2 = Prostaglandin E2; EETs = epoxyeicosatrienoic acids.

Fig. 3 Events that occur in the NVU during CI. As a consequence of a reduction in CBF two processes occur: first, necrosis of neurons, mainly in the core (1) that results in the release of the intracellular content into the interstitial space; this process is partially responsible for microglia activation (2). Second, the BBB becomes abnormally ‘leaky’, which appears as a consequence of a chain of events including degradation of the extracellular matrix (3), detachment of astrocyte end feet from the capillaries (4) and dedifferentiation of capillary endothelial cells with tight junction protein displacement. In some cases, this process enables protein extravasation and infiltration of peripheral macrophages/monocytes and (in some cases) erythrocytes into the brain tissue (5). In addition, some data indicate that pericytes die and contraction (rigor mortis) of their filaments (6) further impede blood flow and limits reperfusion. These processes cause additional activation of microglia (7) and may contribute to neuronal death.

Fig. 4 Summary of microglial activation and polarization after a pathological event (e.g. CI) into the two inflammation-related phenotypes and effects of activated microglia in the ischemic brain. Precise factors that activate microglia and induce polarization into specific phenotypes remain to be identified. Also, it is not known what exactly causes the shift between the two phenotypes, which apparently occurs in vivo (indicated by a question mark).