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The Journal of Neuroscience, July 19, 2006, 26(29):7730-7740; doi:10.1523/JNEUROSCI.1528-06.2006

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Cellular/Molecular
Signaling from Blood Vessels to CNS Axons through Nitric Oxide

Giti Garthwaite, Katalin Bartus, Denise Malcolm, David Goodwin, Martha Kollb-Sielecka, Chaminda Dooldeniya, and John Garthwaite

Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom

Correspondence should be addressed to Giti Garthwaite, Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK. Email: g.garthwaite{at}ucl.ac.uk

Brain function is usually perceived as being performed by neurons with the support of glial cells, the network of blood vessels situated nearby serving simply to provide nutrient and to dispose of metabolic waste. Revising this view, we find from experiments on a rodent central white matter tract (the optic nerve) in vitro that microvascular endothelial cells signal persistently to axons using nitric oxide (NO) derived from the endothelial NO synthase (eNOS). The endogenous NO acts to stimulate guanylyl cyclase-coupled NO receptors in the axons, leading to a raised cGMP level which then causes membrane depolarization, apparently by directly engaging hyperpolarization-activated cyclic nucleotide-gated ion channels. The tonic depolarization and associated endogenous NO-dependent cGMP generation was absent in optic nerves from mice lacking eNOS, although such nerves responded to exogenous NO, with raised cGMP generation in the axons and associated depolarization. In addition to the tonic activity, exposure of optic nerves to bradykinin, a classical stimulator of eNOS in endothelial cells, elicited reversible NO- and cGMP-dependent depolarization through activation of bradykinin B₂ receptors, to which eNOS is physically complexed. No contribution of other NO synthase isoforms to either the action of bradykinin or the continuous ambient NO level could be detected. The results suggest that microvascular endothelial cells participate in signal processing in the brain and can do so by generating both tonic and phasic NO signals.

Key words: endothelial cell; nitric oxide synthase; cGMP; HCN channels; optic nerve; bradykinin

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Received April 9, 2006; revised May 26, 2006; accepted June 12, 2006.

Correspondence should be addressed to Giti Garthwaite, Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK. Email: g.garthwaite{at}ucl.ac.uk

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