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.
Yemisci
Muge
M
Department of Neurology, Faculty of Medicine and Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
Gursoy-Ozdemir
Yasemin
Y
Vural
Atay
A
Can
Alp
A
Topalkara
Kamil
K
Dalkara
Turgay
T
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology* / Q000503:physiopathology*; D002196:Capillaries / Q000503:physiopathology; D048429:Cell Size; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008857:Microscopy, Interference; D020768:Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress; D020286:Pericytes / Q000473:pathology* / Q000502:physiology*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology
D004791:Enzyme Inhibitors; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C065027:N(G)-iminoethylornithine; D009952:Ornithine; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse