Compromised neuro-vascular coupling under blood-brain barrier dysfunction: a role in the pathogenesis of brain diseases?

The brain uses more energy than any other organ of the body and relies almost exclusively on delivery of oxygen (O2) and glucose through the vascular system. A regional increase in the metabolic demands of active neurons is supported by elevated blood flow, a phenomenon termed neuro-vascular coupling (NVC) or functional hyperemia. The blood-brain barrier (BBB) is the regulated interface between the peripheral circulation and the central nervous system (CNS). It's composed of endothelial cells which connected by tight junctions, and together with astrocytes, pericytes, neurons and the extracellular matrix, constitute the
"neurovascular unit" that is essential for proper function of the CNS. Recent recordings in patients with sub-arachnoid hemorrhage demonstrated high incidence of BBB dysfunction together with impaired vascular response during neuronal activation. We thus hypothesized that BBB dysfunction predispose the brain to disturbed neuro-vascular coupling which may further contribute to cellular damage. BBB dysfunction was introduced with either photothrombosis or with exposure of the cortex to artificial "serum like" electrolytic solution containing physiological concentration of albumin, the most common blood protein. Neuro-vascular coupling was tested by imaging vessels diameter changes in the open-window method while corticographic recording of seizures-induced using 4-aminopyridine (4-AP). BBB integrity was estimated using angiography as previously reported. Our results show a pronounced and reversible dilation of cortical vessels during seizures in the healthy brain. In contrast, in the BBB dysfunctional brain (or in the brain exposed to artificial serum), vascular response to neuronal activation was significantly impaired, emphasizing the importance of intact BBB in the normal neuro-vascular coupling.