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VEGF up\u2010regulation after hypoxia coincides with expression of its two tyrosine kinase receptors Flt\u20101(VEGFR\u20101) and Flk\u20101 (KDR\/VEGFR\u20102), which are the key mediators of physiological angiogenesis. We have recently shown that hypoxic\u2010preconditioning (PC) leading to tolerance to hypoxia\u2013ischemia in neonatal piglet brain resulted in increased expression of VEGF. In this study, we used a hypoxic\u2010preconditioning model of ischemic tolerance to analyze the expression and cellular distribution of VEGF receptors and phosphorylation of cAMP\u2010response element\u2010binding protein (CREB) in newborn piglet brain. The response of Flt\u20101 and Flk\u20101 <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> to PC alone was biphasic with peaks early (6\u00a0h) and late (1\u00a0week) after PC. The <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> expression of Flt\u20101 and Flk\u20101 in piglets preconditioned 24\u00a0h prior to hypoxia\u2013ischemia was significantly higher than non\u2010preconditioned piglets and remained up\u2010regulated up to 7\u00a0days. Furthermore, PC prior to hypoxia\u2013ischemia significantly increased the protein levels of Flt\u20101 and Flk\u20101 compared with hypoxia\u2013ischemia in a time\u2010dependent manner. Double\u2010immunolabeling indicated that both Flt\u20101 and Flk\u20101 are expressed in neurons and endothelial cells with a similar time course of expression following PC and that PC leads to the growth of new vessels. Finally, our data demonstrate that PC significantly phosphorylated and activated cAMP\u2010response element\u2010binding protein in nucleus. These results suggest that mechanism(s) initiated by PC can induce VEGF receptor up\u2010regulation in newborn brain and that VEGF\u2013VEGF receptor\u2010coupled signal transduction pathways could contribute to the establishment of tolerance following hypoxia\u2013ischemia.<\/jats:p>","DOI":"10.1111\/jnc.12110","type":"journal-article","created":{"date-parts":[[2012,11,30]],"date-time":"2012-11-30T13:27:49Z","timestamp":1354282069000},"page":"735-746","source":"Crossref","is-referenced-by-count":7,"title":["Enhanced expression of the Flt\u20101 and Flk\u20101 receptor tyrosine kinases in a newborn piglet model of ischemic tolerance"],"prefix":"10.1111","volume":"124","author":[{"given":"Jahan","family":"Ara","sequence":"first","affiliation":[{"name":"Department of Pediatrics Drexel University College of Medicine and Saint Christopher's Hospital for Children Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panchanan","family":"Shukla","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Drexel University College of Medicine and Saint Christopher's Hospital for Children Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Drexel University College of Medicine and Saint Christopher's Hospital for Children Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,1,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-010-0207-2"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.04.021"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-199906000-00007"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-200204000-00003"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2004.00600.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(03)00071-7"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c363"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.18.1.0287"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0603-669"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra041996"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/376066a0"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.38.23659"},{"key":"e_1_2_7_14_1","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrn1927","article-title":"Cerebral preconditioning and ischaemic tolerance","volume":"7","author":"Gidday J. 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