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The disorder is a dangerous urological and hematological emergency since it is associated with ischemic tissue damage and erectile disability. Here we report that phosphodiesterase\u20105 (PDE5) gene expression and PDE activity is significantly reduced in penile tissues of two independent priapic models: SCD mice and adenosine deaminase (ADA)\u2010deficient mice. Moreover, using ADA enzyme therapy to reduce adenosine or a specific antagonist to block A\n                    <jats:sub>2B<\/jats:sub>\n                    adenosine receptor (ADORA2B) signaling, we successfully attenuated priapism in both\n                    <jats:italic>ADA<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    and SCD mice by restoring penile PDE5 gene expression to normal levels. This finding led us to further discover that excess adenosine signaling\n                    <jats:italic>via<\/jats:italic>\n                    ADORA2B activation directly reduces PDE5 gene expression in a hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1)\u2010dependent manner. Overall, we reveal that excess adenosine\u2010mediated ADORA2B signaling underlies reduced penile PDE activity by decreasing PDE5 gene expression in a HIF\u20101\u03b1\u2010dependent manner and provide new insight for the pathogenesis of priapism and novel therapies for the disease.\u2014Ning, C., Wen, J., Zhang, Y., Dai, Y., Wang, W., Zhang, W., Qi, L., Grenz,\n                    <jats:italic>A<\/jats:italic>\n                    ., Eltzschig, H. K., Blackburn, M. R., Kellems, R. E., Xia, Y. Excess adenosine A2B receptor signaling contributes to priapism through HIF\u20101\u03b1 mediated reduction of PDE5 gene expression.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 28, 2725\u20132735 (2014).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.13-247833","type":"journal-article","created":{"date-parts":[[2014,3,10]],"date-time":"2014-03-10T23:17:58Z","timestamp":1394493478000},"page":"2725-2735","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Excess adenosine A2B receptor signaling contributes to priapism through HIF\u20101\u03b1 mediated reduction of PDE5 gene expression"],"prefix":"10.1096","volume":"28","author":[{"given":"Chen","family":"Ning","sequence":"first","affiliation":[{"name":"Department of Biochemistry 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