Key role of tissue plasminogen activator in neurovascular coupling

doi:10.1073/pnas.0708823105

Key role of tissue plasminogen activator in neurovascular coupling

*Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021; and
^†Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10021

Edited by Valina L. Dawson, Johns Hopkins University School of Medicine, Baltimore, MD, and accepted by the Editorial Board December 2, 2007 (received for review September 17, 2007)

Abstract

The increase in blood flow evoked by synaptic activity is essential for normal brain function and underlies functional brain imaging signals. Nitric oxide, a vasodilator released by NMDA receptor activation, is critical for the flow increase, but the factors linking NMDA receptor activity to nitric oxide-dependent hyperemia are poorly understood. Here, we show that tissue plasminogen activator (tPA), a serine protease implicated in NMDA receptor signaling, is required for the flow increase evoked by somatosensory stimulation. tPA acts by facilitating neuronal nitric oxide release, but this effect does not involve enhancement of NMDA currents or the associated intracellular Ca²⁺ rise. Rather, the evidence suggests that tPA controls NMDA-dependent nitric oxide synthesis by influencing the phosphorylation state of neuronal nitric oxide synthase. These findings unveil a previously unrecognized role of tPA in vital homeostatic mechanisms coupling NMDA receptor signaling with nitric oxide synthesis and local cerebral perfusion.

Footnotes

^‡To whom correspondence should be addressed at:
Division of Neurobiology, 411 East 69th Street, Room KB410, New York, NY 10021.
E-mail: coi2001{at}med.cornell.edu
Author contributions: L.P., E.F.G., J.A., G.W., S.S., and C.I. designed research; L.P., E.F.G., J.A., G.W., E.H.N., and J.P. performed research; J.A., G.W., and S.S. contributed new reagents/analytic tools; L.P., J.A., and C.I. analyzed data; and L.P., E.F.G., E.H.N., S.S., and C.I. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. V.L.D. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708823105/DC1.