Here we show that ischemia induces sustained contraction of pericytes on microvessels in the intact mouse brain. Pericytes remain contracted despite successful reopening of the middle cerebral artery after 2 h of ischemia. Pericyte contraction causes capillary constriction and obstructs erythrocyte flow. Suppression of oxidative-nitrative stress relieves pericyte contraction, reduces erythrocyte entrapment and restores microvascular patency; hence, tissue survival improves. In contrast, peroxynitrite application causes pericyte contraction. We also show that the microvessel wall is the major source of oxygen and nitrogen radicals causing ischemia and reperfusion–induced microvascular dysfunction. These findings point to a major but previously not recognized pathophysiological mechanism; ischemia and reperfusion-induced injury to pericytes may impair microcirculatory reflow and negatively affect survival by limiting substrate and drug delivery to tissue already under metabolic stress, despite recanalization of an occluded artery. Agents that can restore pericyte dysfunction and microvascular patency may increase the success of thrombolytic and neuroprotective treatments.
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This work was supported by The Turkish Academy of Sciences (T.D. and Y.G.-O.), Hacettepe University Research Fund 0401105001 (T.D.), Scientific and Technical Research Council of Turkey 104S254 (Y.G.-O.), Ankara University Biotechnology Institute 2001K120240 (A.C.) and Brain Research Association (M.Y.). We are grateful to M.A. Moskowitz for his support and comments. Part of this study was presented at the Society For Neuroscience 37th Annual Meeting in San Diego, California, 2007.
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