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We tested the hypothesis that mitochondrial depolarization stimulates the reparative functions of CD34<jats:sup>+<\/jats:sup> cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Peripheral blood was obtained from healthy individuals (<jats:italic>n<\/jats:italic>\u00a0=\u00a063), and mononuclear cells (MNCs) were separated. MNCs were enriched for lineage negative cells, followed by isolation of CD34<jats:sup>+<\/jats:sup> cells. Vascular repair\u2010relevant functions of CD34<jats:sup>+<\/jats:sup> cells, proliferation and migration, were evaluated in the presence and absence of diazoxide. Mitochondrial membrane potential, ROS and NO levels were evaluated by flow cytometry by using JC\u20101, mitoSOX and DAF\u2010FM respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Diazoxide stimulated the proliferation and migration of CD34<jats:sup>+<\/jats:sup> cells that were comparable to the responses induced by stromal\u2010derived factor\u20101\u03b1 (SDF) or VEGF. Effects of diazoxide were blocked by either 5\u2010hydroxydecanoate (5HD), a selective mitochondrial ATP\u2010sensitive potassium channel (mitoK<jats:sub>ATP<\/jats:sub>) inhibitor, or by L\u2010NAME. Diazoxide induced mitochondrial depolarization, and NO and cGMP generation that were 5HD\u2010sensitive. The generation of NO and cGMP by diazoxide was blocked by an endothelial NOS (eNOS)\u2010selective inhibitor, NIO, but not by a neuronal (n)NOS\u2010selective inhibitor, N<jats:sup>\u03c9<\/jats:sup>\u2010propyl\u2010L\u2010arginine (NPA). A Ca<jats:sup>2+<\/jats:sup> chelator, BAPTA, Akt inhibitor, triciribine, or PI3K inhibitor, LY294002, inhibited the NO release induced by diazoxide. Phosphorylation of eNOS at Ser<jats:sup>1177<\/jats:sup> and dephosphorylation at Thr<jats:sup>495<\/jats:sup> were increased. Diazoxide\u2010induced ROS generation and phosphorylation of eNOS at Ser<jats:sup>1177<\/jats:sup> were reduced by NPA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Diazoxide stimulates vascular repair\u2010relevant functions of CD34<jats:sup>+<\/jats:sup> cells <jats:italic>via<\/jats:italic> the mitoK<jats:sub>ATP<\/jats:sub>\u2010dependent release of NO and ROS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v176.22\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v176.22\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14529","type":"journal-article","created":{"date-parts":[[2018,10,27]],"date-time":"2018-10-27T12:39:19Z","timestamp":1540643959000},"page":"4373-4387","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mitochondrial depolarization stimulates vascular repair\u2010relevant functions of CD34<sup>+<\/sup> cells <i>via<\/i> reactive oxygen species\u2010induced nitric oxide generation"],"prefix":"10.1111","volume":"176","author":[{"given":"Shrinidh","family":"Joshi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Health Professions North Dakota State 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