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      Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes

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          Abstract

          Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

          Key Points

          • Pericytes function as oxygen sensors and are major sites of erythropoietin production in the hypoxic brain.

          • The ability to synthesize erythropoietin is a functional feature of pericytes in the brain and kidney.

          Abstract

          A classic response to systemic hypoxia is the increased production of red blood cells due to hypoxia-inducible factor (HIF)-mediated induction of erythropoietin (EPO). EPO is a glycoprotein hormone that is essential for normal erythropoiesis and is predominantly synthesized by peritubular renal interstitial fibroblast-like cells, which express cellular markers characteristic of neuronal cells and pericytes. To investigate whether the ability to synthesize EPO is a general functional feature of pericytes, we used conditional gene targeting to examine the von Hippel-Lindau/prolyl-4-hydroxylase domain (PHD)/HIF axis in cell-expressing neural glial antigen 2, a known molecular marker of pericytes in multiple organs. We found that pericytes in the brain synthesized EPO in mice with genetic HIF activation and were capable of responding to systemic hypoxia with the induction of Epo. Using high-resolution multiplex in situ hybridization, we determined that brain pericytes represent an important cellular source of Epo in the hypoxic brain (up to 70% of all Epo-expressing cells). We furthermore determined that Epo transcription in brain pericytes was HIF-2 dependent and cocontrolled by PHD2 and PHD3, oxygen- and 2-oxoglutarate–dependent prolyl-4-hydroxylases that regulate HIF activity. In summary, our studies provide experimental evidence that pericytes in the brain have the ability to function as oxygen sensors and respond to hypoxia with EPO synthesis. Our findings furthermore suggest that the ability to synthesize EPO may represent a functional feature of pericytes in the brain and kidney.

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          Author and article information

          Journal
          Blood
          Blood
          bloodjournal
          blood
          Blood
          Blood
          American Society of Hematology (Washington, DC )
          0006-4971
          1528-0020
          24 November 2016
          28 September 2016
          24 November 2017
          : 128
          : 21
          : 2550-2560
          Affiliations
          [1 ]Department of Medicine and
          [2 ]Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN;
          [3 ]Medical and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, TN;
          [4 ]Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY; and
          [5 ]Departments of Cancer Biology and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
          Author information
          http://orcid.org/0000-0001-7945-5515
          http://orcid.org/0000-0001-6406-2233
          http://orcid.org/0000-0002-7051-8994
          Article
          PMC5123193 PMC5123193 5123193 2016/713545
          10.1182/blood-2016-05-713545
          5123193
          27683416
          1e30fdd7-44c3-481b-a8c2-e0eda485f52e
          Copyright @ 2016
          History
          : 02 May 2016
          : 22 September 2016
          Page count
          Pages: 11
          Funding
          Funded by: National Institutes of Health;
          Categories
          36
          Red Cells, Iron, and Erythropoiesis

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