Hypothetical model of Neurovascular Unit function (NVU) (A) and dysfunction in an acute MS lesion (B) and a chronic end-stage lesion (C). (A) Composition of blood–brain barrier (BBB)-provided microvessels, formed by endothelial cells which are connected by tight junctions (TJ), pericytes, astrocyte endfeet, and a continuous layer of basement membrane (BM). Neurovascular coupling is brought about by astrocyte processes which remove excess K+ ions at active synaptic spaces and release these ions into perivascular spaces; at the same time Glutamate (Glu) bound to astrocyte receptors can increase astrocytic Ca++ levels and produce vasodilatatory substances. Microglia and oligodendrocyte precursor cells (OPCs) contribute to NVU function. (B) An acute MS lesion, dominated by high levels of VEGF and other angiogenic molecules, shows BBB leakiness, vasogenic swelling of BM and disrupted NVU interactions: claudin-5 and occludin, two TJ proteins, are mislocalized and downregulated; the BM is degraded by MMPs, mainly released by leukocytes infiltrating vessel BM; microglia are activated and release large amounts of pro-inflammatory mediators; astrocyte endfeet are detached from pericytes. Activated B lymphocytes release self-targeted antibodies damaging myelinated axons. (C) Chronic end-stage MS lesion dominated by hypoperfusion, and persistence of an inflammatory milieu with abundant reactive oxygen species (ROS), peroxynitrite (RNS) and stress-associated proteins, all together inhibiting the net pro-angiogenic activity. The drawing shows pro-inflammatory microglia and also the influence of demyelination on reduced axonal activities, decreased vasodilatatory stimuli and consequent vasoconstriction. Hypoperfusion is also due to vessel wall hyalinization, collagen deposition and astrocyte endfeet hypertrophy. Persistent inflammation is also responsible for endothelial-derived protective molecules and growth factors downregulation which, in turn, maintains neural stem cells (NSC) in a resting state and impedes neuroblast and OPC maturation in the neurovascular niches in the subependymal layer of the lateral ventricle (LV) and in other neuroregenerative sites around blood microvessels.