title: Human HtrA4 Expression Is Restricted to the Placenta, Is Significantly Up-Regulated in Early-Onset Preeclampsia, and High Levels of HtrA4 Cause Endothelial Dysfunction.
abstract: BACKGROUND
  Preeclampsia (PE), a pregnancy-specific disorder closely associated with endothelial dysfunction and capillary leakage, is responsible for substantial maternal/fetal morbidity and mortality. PE can be classified as early-onset (<34 wk) and late-onset (>34 wk); the two subsets differ in presentation and pathogenesis.
  
  
  OBJECTIVE
  The objectives of the study were to examine serine protease high-temperature requirement factor A4 (HtrA4) expression in the placenta and other human tissues and in early-onset vs late-onset PE, to determine serum HtrA4 levels in normal pregnancy and in PE subtypes, and to investigate the effect of high levels of HtrA4 on endothelial integrity and function.
  
  
  METHODS
  Microarray data analysis and RT-PCR determined HtrA4 expression in the human placenta, various tissues, and cell lines. The serum HtrA4 protein levels were analyzed by an ELISA. The potential impact of excessive circulating HtrA4 on the maternal vasculature was determined by in vitro endothelial tube and permeability assays.
  
  
  RESULTS
  Human HtrA4 expression was restricted to the placenta and significantly up-regulated in early-onset but not late-onset PE. The serum HtrA4 levels in normal pregnancy increased significantly between the first and second trimesters and then remained constant. Women with early-onset but not late-onset PE showed significantly higher HtrA4 levels in serum compared with gestational age-matched controls. In cell models, high levels of HtrA4 disturbed endothelial cell tube formation and permeability in a dose-dependent manner, and this was linked to alterations in junctional proteins and microtubule organization.
  
  
  CONCLUSIONS
  HtrA4 represents a novel placenta-specific serine protease that is altered specifically in early-onset PE with potential causal roles in endothelial dysfunction and disease development.
authors.affiliation: Implantation and Placental Developmental Laboratory (H.S., Y.W., Y.L., G.N.), Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University (H.S., Y.W., Y.L., G.N.), Clayton, Victoria 3800, Australia; Wuxi Maternity and Children's Health Hospital (M.Z., Q.C.), Nanjing Medical University, Jiangsu 214002, China; Department of Obstetrics and Gynaecology (Q.C.), University of Auckland, 1142 Auckland, New Zealand; and Department of Obstetrics and Gynaecology (T.J.K.-L., S.T.), Mercy Hospital for Women, Heidelberg, Victoria 3084, Australia.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Singh
authors.affiliation: Implantation and Placental Developmental Laboratory (H.S., Y.W., Y.L., G.N.), Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University (H.S., Y.W., Y.L., G.N.), Clayton, Victoria 3800, Australia; Wuxi Maternity and Children's Health Hospital (M.Z., Q.C.), Nanjing Medical University, Jiangsu 214002, China; Department of Obstetrics and Gynaecology (Q.C.), University of Auckland, 1142 Auckland, New Zealand; and Department of Obstetrics and Gynaecology (T.J.K.-L., S.T.), Mercy Hospital for Women, Heidelberg, Victoria 3084, Australia.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Implantation and Placental Developmental Laboratory (H.S., Y.W., Y.L., G.N.), Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University (H.S., Y.W., Y.L., G.N.), Clayton, Victoria 3800, Australia; Wuxi Maternity and Children's Health Hospital (M.Z., Q.C.), Nanjing Medical University, Jiangsu 214002, China; Department of Obstetrics and Gynaecology (Q.C.), University of Auckland, 1142 Auckland, New Zealand; and Department of Obstetrics and Gynaecology (T.J.K.-L., S.T.), Mercy Hospital for Women, Heidelberg, Victoria 3084, Australia.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Implantation and Placental Developmental Laboratory (H.S., Y.W., Y.L., G.N.), Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University (H.S., Y.W., Y.L., G.N.), Clayton, Victoria 3800, Australia; Wuxi Maternity and Children's Health Hospital (M.Z., Q.C.), Nanjing Medical University, Jiangsu 214002, China; Department of Obstetrics and Gynaecology (Q.C.), University of Auckland, 1142 Auckland, New Zealand; and Department of Obstetrics and Gynaecology (T.J.K.-L., S.T.), Mercy Hospital for Women, Heidelberg, Victoria 3084, Australia.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Implantation and Placental Developmental Laboratory (H.S., Y.W., Y.L., G.N.), Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University (H.S., Y.W., Y.L., G.N.), Clayton, Victoria 3800, Australia; Wuxi Maternity and Children's Health Hospital (M.Z., Q.C.), Nanjing Medical University, Jiangsu 214002, China; Department of Obstetrics and Gynaecology (Q.C.), University of Auckland, 1142 Auckland, New Zealand; and Department of Obstetrics and Gynaecology (T.J.K.-L., S.T.), Mercy Hospital for Women, Heidelberg, Victoria 3084, Australia.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Implantation and Placental Developmental Laboratory (H.S., Y.W., Y.L., G.N.), Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University (H.S., Y.W., Y.L., G.N.), Clayton, Victoria 3800, Australia; Wuxi Maternity and Children's Health Hospital (M.Z., Q.C.), Nanjing Medical University, Jiangsu 214002, China; Department of Obstetrics and Gynaecology (Q.C.), University of Auckland, 1142 Auckland, New Zealand; and Department of Obstetrics and Gynaecology (T.J.K.-L., S.T.), Mercy Hospital for Women, Heidelberg, Victoria 3084, Australia.
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
authors.affiliation: Implantation and Placental Developmental Laboratory (H.S., Y.W., Y.L., G.N.), Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University (H.S., Y.W., Y.L., G.N.), Clayton, Victoria 3800, Australia; Wuxi Maternity and Children's Health Hospital (M.Z., Q.C.), Nanjing Medical University, Jiangsu 214002, China; Department of Obstetrics and Gynaecology (Q.C.), University of Auckland, 1142 Auckland, New Zealand; and Department of Obstetrics and Gynaecology (T.J.K.-L., S.T.), Mercy Hospital for Women, Heidelberg, Victoria 3084, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
authors.affiliation: Implantation and Placental Developmental Laboratory (H.S., Y.W., Y.L., G.N.), Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University (H.S., Y.W., Y.L., G.N.), Clayton, Victoria 3800, Australia; Wuxi Maternity and Children's Health Hospital (M.Z., Q.C.), Nanjing Medical University, Jiangsu 214002, China; Department of Obstetrics and Gynaecology (Q.C.), University of Auckland, 1142 Auckland, New Zealand; and Department of Obstetrics and Gynaecology (T.J.K.-L., S.T.), Mercy Hospital for Women, Heidelberg, Victoria 3084, Australia.
authors.forename: Guiying
authors.initials: G
authors.lastname: Nie
mesh_terms: D017668:Age of Onset; D016022:Case-Control Studies; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D020869:Gene Expression Profiling; D005865:Gestational Age; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D046228:Microarray Analysis; D009928:Organ Specificity / Q000235:genetics; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000235:genetics* / Q000503:physiopathology; D057057:Serine Proteases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: C576189:HtrA4 protein, human; D057057:Serine Proteases