Figure 1.

NVU in cerebral ischemia includes a closely coupled signaling network of ECs, pericytes, astrocytes and neurons. Neurovascular uncoupling consists of the expression of various cytokines and adhesion molecules on ECs, promoting leukocyte adherence and accumulation, which thereby initiates an inflammatory response. Further, breakdown of the BBB via NO, MMPs and ROS permits neutrophil extravasation into the ischemic tissue in response to chemokines produced by astrocytes, macrophages, and microglia. Glutamate-mediated excitotoxicity via NMDA and AMPA receptors induces the hyperstimulation of neurons and subsequent calcium influx, indicating several intracellular calcium stores (mitochondria and ER), which triggers dendritotoxic and cell death pathways. Intrinsic neurovascular responses after stroke are triggered by astrocytes via the spread of calcium waves, promoting homeostatic gliotransmission. In addition, glutamate uptake by astrocytes, which requires EAATs, represents the primary neuroprotective response after excitotoxicity. Alternatively, K⁺ and glucose uptake and insulin and albumin transport signal the modulation of neurovascular homeostasis. Tight junctions (TJs) consisting of claudins, occludins and JAM and adherens junctions (AJ) including members of the cadherin-catenin system maintain the integrity of the endothelium. Cell–cell adhesion may transmit intracellular signals that regulate paracellular permeability, contact-induced inhibition of cell growth and new vessel formation. After stroke, pericytes display deformed junctions and increased formation of pinocytic vesicles, which affect the polarization of astrocyte end-feet (AF), detected as the defective deposition of the astrocyte-derived basement membrane (aBM). Deposition of the endothelium-derived basement membrane (eBM) is affected by the lack of pericytes. Moreover, modifications of the molecular organization and intracellular signaling of junction proteins may exert complex effects on vascular homeostasis.