Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes.
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.
Department of Medicine and.
Andres A
0000-0001-7945-5515
AA
Urrutia
Department of Medicine and.|Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN.
Aqeela
0000-0001-6406-2233
A
Afzal
Department of Medicine and.
Jacob
J
Nelson
Department of Medicine and.|Medical and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, TN.
Olena
O
Davidoff
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY; and.
Kenneth W
KW
Gross
Department of Medicine and.|Medical and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, TN.|Departments of Cancer Biology and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
Volker H
0000-0002-7051-8994
VH
Haase
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D002534:Hypoxia, Brain / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020286:Pericytes / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
C485502:HIF-2 protein, mouse; D014157:Transcription Factors; D004921:Erythropoietin; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
Eur J Haematol. 2007 Mar;78(3):183-205
17253966
Science. 2001 Apr 20;292(5516):468-72
11292861
Development. 2005 Dec;132(23):5317-28
16284122
Mol Cell Biol. 2015 Aug;35(15):2658-72
26012551
Int J Dev Neurosci. 2011 Oct;29(6):655-61
21704147
Genes Dev. 2014 Oct 15;28(20):2189-204
25319824
J Clin Invest. 2016 Apr 1;126(4):1425-37
26927670
Brain. 2002 Nov;125(Pt 11):2549-57
12390979
Eur J Neurosci. 1996 Apr;8(4):666-76
9081618
Mol Cell Biol. 2006 Nov;26(22):8336-46
16966370
Blood Rev. 2013 Jan;27(1):41-53
23291219
Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):654-9
16407130
Science. 2001 Apr 20;292(5516):464-8
11292862
Blood. 2013 Feb 21;121(8):1436-45
23264599
Blood. 2010 Oct 21;116(16):3039-48
20628150
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16626-30
18922767
Blood. 2008 May 15;111(10 ):5223-32
18202227
Am J Physiol. 1992 Sep;263(3 Pt 2):F474-81
1415576
Nat Rev Neurosci. 2005 Jun;6(6):484-94
15928718
Dev Cell. 2011 Aug 16;21(2):193-215
21839917
J Biol Chem. 2004 Sep 10;279(37):38458-65
15247232
Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16805-10
19805377
J Pathol. 2008 Mar;214(4):482-8
18189331
Nat Neurosci. 2011 Oct 26;14(11):1398-405
22030551
Hepatology. 2011 Mar;53(3):983-95
21294146
Cell. 2001 Oct 5;107(1):43-54
11595184
Dev Biol. 1996 Mar 15;174(2):221-32
8631495
Mol Neurodegener. 2010 Aug 25;5:32
20738866
J Am Soc Nephrol. 2016 Feb;27(2):428-38
26054543
Nature. 2002 Jun 27;417(6892):975-8
12050673
Nat Rev Neurosci. 2009 Jan;10(1):9-22
19096367
Clin Exp Pharmacol Physiol. 2000 May-Jun;27(5-6):422-7
10831247
Blood. 2003 Sep 1;102(5):1634-40
12750163
Dev Dyn. 2001 Oct;222(2):218-27
11668599
J Clin Invest. 2007 Apr;117(4):1068-77
17404621
J Neurosci. 2006 Sep 13;26(37):9471-81
16971531
Science. 2010 Jul 23;329(5990):407
20651146
J Clin Invest. 2009 Nov;119(11):3373-83
19809162
Glia. 2000 May;30(3):271-8
10756076
Front Neurosci. 2014 Jun 27;8:133
25018689
Nature. 2013 Oct 31;502(7473):637-43
24107994
Physiology (Bethesda). 2015 Sep;30(5):340-8
26328879
Development. 2008 Jan;135(1):145-57
18045844
Genesis. 2012 Jun;50(6):506-15
22173870
Nature. 2010 Nov 25;468(7323):562-6
20944625
Blood. 2008 Mar 15;111(6):3229-35
18056838
Blood. 2008 Mar 15;111(6):3236-44
18096761
Mol Cell. 2008 May 23;30(4):393-402
18498744
J Cereb Blood Flow Metab. 2010 Apr;30(4):837-48
19997118
Nature. 2010 Nov 25;468(7323):557-61
20944627
J Clin Invest. 2011 Oct;121(10):3981-90
21911936
J Clin Invest. 2016 May 2;126(5):1926-38
27088801
FASEB J. 2012 May;26(5):1831-4
22321729
Sci STKE. 2005 Oct 18;2005(306):re12
16234508
Neuron. 2015 Jul 1;87(1):95-110
26119027
Neurophotonics. 2015 Oct;2(4):041402
26158016
Nature. 2014 Apr 3;508(7494):55-60
24670647
J Neurocytol. 2002 Jul-Aug;31(6-7):423-35
14501214
J Clin Invest. 2012 Dec;122(12 ):4635-44
23114598
Blood. 2013 Aug 15;122(7):1122-8
23733342
Nat Genet. 2014 Sep;46(9):951-6
25129147
Haematologica. 2012 Jan;97(1):123-7
21828119
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10526-31
10984541
Mol Cell Biol. 2009 Nov;29(21):5729-41
19720742
Mol Psychiatry. 2004 Jan;9(1):42-54
14581931
J Cereb Blood Flow Metab. 1999 Jun;19(6):643-51
10366194
Nat Rev Nephrol. 2015 Jul;11(7):394-410
26055355