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Circulation. 2015 Feb 24;131(8):730-41. doi: 10.1161/CIRCULATIONAHA.114.013740. Epub 2014 Dec 23.

Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia.

Author information

1
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.).
2
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.

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.

METHODS AND 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.

KEYWORDS:

adenosine; hypertension; models, animal; preeclampsia; pregnancy

PMID:
25538227
PMCID:
PMC4751998
DOI:
10.1161/CIRCULATIONAHA.114.013740
[Indexed for MEDLINE]
Free PMC Article

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