Local Ischemia in the Neurovascular Unit (NVU) as a Primary Driver of Blood-Brain Barrier (BBB) Breakdown in Multiple Sclerosis

Multiple Sclerosis (MS) is classically characterized as an autoimmune disorder where autoreactive immune cells breach the blood-brain barrier (BBB) to initiate inflammatory demyelination. However, the precise mechanisms driving the initial breakdown of the neurovascular unit (NVU) remain contentious. This paper advances the hypothesis that localized microvascular ischemia, provoked by pericyte-mediated capillary constriction or transient microthrombosis, serves as the primary upstream trigger for BBB dysfunction. Under hypoxic conditions, the stabilization of hypoxia-inducible factor 1-alpha (HIF-1alpha) and subsequent upregulation of vascular endothelial growth factor (VEGF) disrupt endothelial tight junctions, facilitating secondary immune infiltration. Reframing BBB breakdown as an ischemia-driven phenomenon highlights microvascular stabilization and pericyte signaling as promising therapeutic avenues to impede lesion development in MS.