title: Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia.
abstract: BACKGROUND
  Preeclampsia is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be caused by placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways that lead to impaired placentas and maternal disease development remain elusive.
  
  
  RESULTS
  Using 2 independent animal models of preeclampsia (genetically engineered pregnant mice with elevated adenosine exclusively in placentas and a pathogenic autoantibody-induced preeclampsia mouse model), we demonstrated that chronically elevated placental adenosine was sufficient to induce hallmark features of preeclampsia, including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacological approaches revealed that elevated placental adenosine coupled with excessive A₂B adenosine receptor (ADORA2B) signaling contributed to the development of these features of preeclampsia. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental adenosine, thereby contributing to preeclampsia.
  
  
  CONCLUSIONS
  We determined that elevated placental adenosine signaling is a previously unrecognized pathogenic factor for preeclampsia. Moreover, our findings revealed the molecular basis underlying the elevation of placental adenosine and the detrimental role of excess placental adenosine in the pathophysiology of preeclampsia, and thereby, we highlight novel therapeutic targets.
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iriyama
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Sun
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parchim
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Li
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Anren
authors.initials: A
authors.lastname: Song
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Laura A
authors.initials: LA
authors.lastname: Hart
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Sean C
authors.initials: SC
authors.lastname: Blackwell
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Baha M
authors.initials: BM
authors.lastname: Sibai
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Lee-Nien L
authors.initials: LN
authors.lastname: Chan
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Teh-Sheng
authors.initials: TS
authors.lastname: Chan
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.).
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: From Departments of Biochemistry and Molecular Biology (T.I., K.S., N.F.P., J.L., C.Z., A.S., M.R.B., R.E.K., Y.X.) and Department of Obstetrics, Gynecology, and Reproductive Sciences (L.A.H., S.C.B., B.M.S.), University of Texas Medical School at Houston: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan (T.I.); Graduate School of Biomedical Sciences, University of Texas, Houston (K.S., N.F.P., M.R.B, R.E.K., Y.X.); Department of Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, (L-N. L.C., T.-S.C.); and Department of Pathology, Texas Children's Hospital, Houston (M.J.H.). yang.xia@uth.tmc.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000503:physiopathology; D017353:Gene Deletion; D006801:Humans; D018345:Mice, Knockout; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology*; D011247:Pregnancy; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D043704:Receptor, Adenosine A2B; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D015720:5'-Nucleotidase; D000243:Adenosine Deaminase; D000241:Adenosine
keywords: adenosine; hypertension; models, animal; preeclampsia; pregnancy