Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery


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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Figure 1: Ischemia and reperfusion induces segmental narrowing of capillaries due to sustained contraction of pericytes.
Figure 2: Ischemic pericytes contract and hence constrict the adjoining capillary.
Figure 3: Suppression of oxidative-nitrative stress during reperfusion relieves pericyte contraction and restores microvascular patency.
Figure 4: Ischemia- or peroxynitrite-induced pericyte contraction colocalize with 3-nitrotyrosine immunolabeling.
Figure 5: Despite successful recirculation, capillaries in the MCA territory were filled with trapped erythrocytes.
Figure 6: Effects of ischemia and peroxynitrite on microvessels visualized with FITC-dextran and monitored through a cranial window.


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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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M.Y. performed the in vivo experiments and histology studies and contributed to the in vitro studies, design of the experiments, data analyses and preparation of the figures; Y.G.-O. conducted and performed the intravital microscopy experiments and in vitro studies and contributed to the histology studies, design of the experiments and preparation of the figures; A.V. contributed to the intravital microscopy experiments and in vitro studies, performed image analyses and contributed to the preparation of the figures; A.C. conducted the confocal and DIC microscopy studies and prepared the figures; K.T. contributed to the in vivo experiments and performed the in vivo experiments with knockout mice; T.D. designed and supervised the project, contributed to the data analyses and wrote the manuscript.

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Correspondence to Turgay Dalkara.

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Yemisci, M., Gursoy-Ozdemir, Y., Vural, A. et al. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med 15, 1031–1037 (2009).

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