Zhang D, Ruan J, Peng S, Li J, Hu X, Zhang Y, Zhang T, Ge Y, Zhu Z, Xiao X, Zhu Y, Li X, Li T, Zhou L, Gao Q, Zheng G, Zhao B, Li X, Zhu Y, Wu J, Li W, Zhao J, Ge WP, Xu T, Jia JM. Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling. Nat Neurosci. 2024 Jan 2; PubMed.
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Rush University Medical Center
The term neurovascular coupling was coined in 2001 to indicate the interaction between brain activity and brain blood supply. While approximately a century ago it was believed that the vessels supplying blood to the brain and the brain cells function independently, neurovascular coupling evolved over time to highlight how the brain engages in regulating its own blood supply. Multiple mechanisms have been suggested and investigated that underlie neurovascular coupling.
Here the investigators suggest a new mechanism for mediation of neurovascular coupling. By leveraging novel techniques, they showed that: 1) there are gaps in the astrocytic end feet that surround arterioles. 2) In these gaps, there are presynaptic axonal boutons that lie in the vicinity of underlying smooth muscle cells. 3) The axonal boutons are glutamatergic. 4) The smooth muscle cells participating in the junction with the boutons have glutamatergic receptors. 5) Activation of the glutamatergic receptors with small doses of glutamate, an indication of neural activity, is accompanied by calcium influx, which results in efflux of potassium, hyperpolarization and relaxation of smooth muscle cells, and vasodilation.
The investigators also showed that profound release of glutamate, in pathologic conditions such as stroke, results in over-influx of calcium and contraction of smooth muscle cells, which dampens blood flow to already hypoxic brain cells and accentuates neural loss.
The findings are very intriguing as they extend possible mechanisms underlying neurovascular coupling. The findings are presented by fascinating images of the cerebral vessels illustrating the gaps in astrocytic end feet and localization of neural-arteriolar smooth muscle junctions and related receptors.
Several experimental models and tests were done to support study findings and conclusions. However, the main study findings are derived from experimental animal studies and cell cultures, which limits generalizability to human. Future human studies are needed to confirm expression of glutamate receptors in smooth muscle cells of cerebral small vessels. Moreover, more comparative studies are needed to elucidate the effect size of this mechanism in neurovascular coupling compared with other mechanisms including endothelial-derived vasodilators in both physiological and pathological conditions.
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