Purinergic mechanisms in gliovascular coupling

Abstract

Regional elevations in cerebral blood flow (CBF) often occur in response to localized increases in cerebral neuronal activity. An ever expanding literature has linked this neurovascular coupling process to specific signaling pathways involving neuronal synapses, astrocytes and cerebral arteries and arterioles. Collectively, these structures are termed the "neurovascular unit" (NVU). Astrocytes are thought to be the cornerstone of the NVU. Thus, not only do astrocytes "detect" increased synaptic activity, they can transmit that information to proximal and remote astrocytic sites often through a Ca 2+ -and ATP-related signaling process. At the vascular end of the NVU, a Ca 2+ -dependent formation and release of vasodilators, or substances linked to vasodilation, can occur. The latter category includes ATP, which upon its appearance in the extracellular compartment, can be rapidly converted to the potent vasodilator, adenosine, via the action of ectonucleotidases. In the present review, we give consideration to experimental model-specific variations in purinergic influences on gliovascular signaling mechanisms, focusing on the cerebral cortex. In that discussion, we compare findings obtained using in vitro (rodent brain slice) models and multiple in vivo models (2-photon imaging; somatosensory stimulation-evoked cortical hyperemia; and sciatic nerve stimulation-evoked pial arteriolar dilation). Additional attention is given to the importance of upstream (remote) vasodilation; the key role played by extracellular ATP hydrolysis (via ecto-nucleotidases) in gliovascular coupling; and interactions among multiple signaling pathways.

Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

“…Transient withdrawal of glucose, the major energy substrate for neurons, as well as removal of amino acids from the culture medium results in mitochondrial depolarization, reduced ATP production, and the development of delayed tolerance against various insults, such as OGD, glutamate excitotoxicity, and exogenous hydrogen peroxide (63). Breakdown products of ATP: adenosine, AMP, ADP, as well as ATP itself, are vasoactive stimuli in cerebral arteries (36,123).…”

Pathophysiology of astroglial purinergic signalling

“…It should be noted that P2Y 1 Rs, found on the glia limitans and on vascular endothelium, are also important for ischaemic regulatory processes; for example, endothelial P2Y 2 Rmediated dilatations of rat middle cerebral artery in response to uridine-5′-triphosphate (UTP) were potentiated after ischaemia-reperfusion, while P2Y 1 R-mediated dilatation was simultaneously attenuated [206,207]. Not only purine but also pyrimidine nucleotides appear to be released during ischaemia; the UTP-induced activation of P2Y 4 Rs causes cell death in human neuroblastoma cells [208].…”

Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia

“…For example, studies using human umbilical vein endothelial cells showed that these cells could develop BBB properties when cocultured with astrocytes, which implies that astrocytes secrete trophic factors critical to maintenance of the BBB phenotype (Hayashi et al, 1997). Astrocytes may be involved in transient regulation of cerebral microvascular permeability (Ballabh et al, 2004), in particular via dynamic Ca 2+ signaling between astrocytes and the endothelium via gap junctions and purinergic transmission (Goldberg et al, 2010;Pelligrino et al, 2011). Recent evidence also suggests that astrocytes may play a critical role in regulating water and ion exchange across the brain microvascular endothelium (Abbott et al, 2006;Mathiisen et al, 2010).…”