title: Complement-mediated macrophage polarization in perivascular adipose tissue contributes to vascular injury in deoxycorticosterone acetate-salt mice.
abstract: OBJECTIVE
  We have previously shown an increased expression of complement 3 (C3) in the perivascular adipose tissue (PVAT) in the deoxycorticosterone acetate (DOCA)-salt hypertensive model. This study aims to examine the role and underlying mechanism of C3 in PVAT for understanding the pathogenesis of hypertensive vascular remodeling further.
  
  
  RESULTS
  The role of C3 in macrophage polarization was investigated using peritoneal macrophages from wild-type and C3-deficient (C3KO) mice because we found that C3 was primarily expressed in macrophages in PVAT of blood vessels from DOCA-salt mice, and results showed a decreased expression of M1 phenotypic marker in contrast to an increased level of M2 marker in the C3KO macrophages. Bone marrow transplantation studies further showed in vivo that DOCA-salt recipient mice had fewer M1 but more M2 macrophages in PVAT when the donor bone marrows were from C3KO compared with those from wild-type mice. Of note, this macrophage polarization shift was accompanied with an ameliorated vascular injury. Furthermore, we identified the complement 5a (C5a) as the major C3 activation product that was involved in macrophage polarization and DOCA-salt-induced vascular injury. Consistently, in vivo depletion of macrophages prevented the induction of C3 and C5a in PVAT, and ameliorated hypertensive vascular injury as well.
  
  
  CONCLUSIONS
  The presence and activation of bone marrow-derived macrophages in PVAT are crucial for complement activation in hypertensive vascular inflammation, and C5a plays a critical role in DOCA-salt-induced vascular injury by stimulating macrophage polarization toward a proinflammatory M1 phenotype in PVAT.
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Cheng-Chao
authors.initials: CC
authors.lastname: Ruan
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Qian
authors.initials: Q
authors.lastname: Ge
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Dong-Rui
authors.initials: DR
authors.lastname: Chen
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Kai-Da
authors.initials: KD
authors.lastname: Ji
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Sheng
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.).
authors.forename: Ding-Liang
authors.initials: DL
authors.lastname: Zhu
authors.affiliation: From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., Q.G., Y.L., X.-D.L., D.-R.C., K.-D.J., Y.-J.W., L.-J.S., D.-L.Z., P.-J.G.); Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.-C.R., P.-J.G.); and Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (C.Y.). gaopingjin@sibs.ac.cn.
authors.forename: Ping-Jin
authors.initials: PJ
authors.lastname: Gao
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000276:immunology / Q000378:metabolism; D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D016026:Bone Marrow Transplantation; D002450:Cell Communication; D003167:Complement Activation; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015936:Complement C5a / Q000378:metabolism*; D064791:Desoxycorticosterone Acetate; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors; D014652:Vascular Diseases / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D066253:Vascular Remodeling
chemical_list: C545610:C3 protein, mouse; D003176:Complement C3; D008070:Lipopolysaccharides; D064791:Desoxycorticosterone Acetate; D015936:Complement C5a
keywords: complement; macrophage polarization; perivascular adipose tissue; vascular injury