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Przybyl L, Haase N, Golic M, Rugor J, Solano ME, Arck PC, Gauster M, Huppertz B, Emontzpohl C, Stoppe C, Bernhagen J, Leng L, Bucala R, Schulz H, Heuser A, Weedon-Fekjær MS, Johnsen GM, Peetz D, Luft FC, Staff AC, Müller DN, Dechend R, Herse F. CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia. Circ Res 2016; 119:55-68. [PMID: 27199465 DOI: 10.1161/circresaha.116.308304] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 05/19/2016] [Indexed: 01/28/2023]
Abstract
RATIONALE We hypothesized that cluster of differentiation 74 (CD74) downregulation on placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia. OBJECTIVE Preeclamptic pregnancies feature hypertension, proteinuria, and placental anomalies. Feto-placental macrophages regulate villous trophoblast differentiation during placental development. Disturbance of this well-balanced regulation can lead to pathological pregnancies. METHODS AND RESULTS We performed whole-genome expression analysis of placental tissue. CD74 was one of the most downregulated genes in placentas from preeclamptic women. By reverse transcriptase-polymerase chain reaction, we confirmed this finding in early-onset (<34 gestational week, n=26) and late-onset (≥34 gestational week, n=24) samples from preeclamptic women, compared with healthy pregnant controls (n=28). CD74 protein levels were analyzed by Western blot and flow cytometry. We identified placental macrophages to express CD74 by immunofluorescence, flow cytometry, and RT-PCR. CD74-positive macrophages were significantly reduced in preeclamptic placentas compared with controls. CD74-silenced macrophages showed that the adhesion molecules ALCAM, ICAM4, and Syndecan-2, as well as macrophage adhesion to trophoblasts were diminished. Naive and activated macrophages lacking CD74 showed a shift toward a proinflammatory signature with an increased secretion of tumor necrosis factor-α, chemokine (C-C motif) ligand 5, and monocyte chemotactic protein-1, when cocultured with trophoblasts compared with control macrophages. Trophoblasts stimulated by these factors express more CYP2J2, sFlt1, TNFα, and IL-8. CD74-knockout mice showed disturbed placental morphology, reduced junctional zone, smaller placentas, and impaired spiral artery remodeling with fetal growth restriction. CONCLUSIONS CD74 downregulation in placental macrophages is present in preeclampsia. CD74 downregulation leads to altered macrophage activation toward a proinflammatory signature and a disturbed crosstalk with trophoblasts.
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Affiliation(s)
- Lukasz Przybyl
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Nadine Haase
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Michaela Golic
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Julianna Rugor
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Maria Emilia Solano
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Petra Clara Arck
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Martin Gauster
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Berthold Huppertz
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Christoph Emontzpohl
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Christian Stoppe
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Jürgen Bernhagen
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Lin Leng
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Richard Bucala
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Herbert Schulz
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Arnd Heuser
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - M Susanne Weedon-Fekjær
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Guro M Johnsen
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Dirk Peetz
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Friedrich C Luft
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Anne Cathrine Staff
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Dominik N Müller
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Ralf Dechend
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.)
| | - Florian Herse
- From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.).
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