title: Gelsolin is an endogenous inhibitor of syncytiotrophoblast extracellular vesicle shedding in pregnancy.
abstract: BACKGROUND
  Preeclampsia, a pregnancy-specific inflammatory disorder, is characterized by high levels of anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), in the maternal circulation. sFlt1 producing molecular machinery is present in syncytiotrophoblast extracellular vesicles that are released by the placenta into maternal plasma during normal pregnancy, a process greatly accelerated in preeclampsia. We hypothesized that syncytiotrophoblast extracellular vesicles exposes cytoplasmic actin to plasma resulting in depletion of plasma gelsolin (pGSN), an abundant plasma protein that scavenges circulating actin and other pro-inflammatory mediators.
  
  
  OBJECTIVE
  To test whether pGSN levels would be lower in preeclampsia and to assess whether recombinant human plasma gelsolin (rhpGSN) may promote placental health by decreasing shedding of syncytiotrophoblast extracellular vesicles.
  
  
  METHODS
  We tested pGSN levels in third trimester plasma samples from women with preeclampsia and non-hypertensive pregnancies. We then assessed whether rhpGSN may act as a negative regulator of syncytial shedding in placental explant culture and dynamic mechanical stretch studies.
  
  
  RESULTS
  pGSN levels fall in late pregnancy and decline further in preeclampsia patients. Recombinant human pGSN (rhpGSN) at 100μg/ml limits spontaneous syncytiotrophoblast vesicle release and sFlt1 protein dissemination by normal placental explants. Higher rhpGSN doses (500μg/ml) also limit syncytiotrophoblast vesicle and sFlt1 dissemination from preeclamptic placental explants. rhpGSN also mitigates syncytiotrophoblast vesicle during dynamic mechanical stretch.
  
  
  CONCLUSIONS
  1) pGSN, an anti-inflammatory factor of maternal origin is reduced in preeclampsia and may contribute to disease progression and 2) exogenous rhpGSN supplementation can limit the dissemination of toxic syncytiotrophoblast vesicle that characterizes the disease state.
authors.affiliation: Department of Neurology, McGaw Northwestern Memorial Hospital, Chicago, IL, United States; Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Nadkarni
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Department of Obstetrics and Gynecology, Emory University School of Medicine, Atlanta, GA, United States.
authors.forename: Augustine
authors.initials: A
authors.lastname: Rajakumar
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Nikita
authors.initials: N
authors.lastname: Mokhashi
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Burke
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology University of Chicago, Chicago, IL, United States; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Beth Israel Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Sarosh
authors.initials: S
authors.lastname: Rana
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Beth Israel Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Saira
authors.initials: S
authors.lastname: Salahuddin
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Department of Emergency Medicine, Beth Israel Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Quynh
authors.initials: Q
authors.lastname: Dang
authors.affiliation: Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Thadhani
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Department of Emergency Medicine, Beth Israel Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Krishnan
authors.affiliation: Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Stossel
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Beth Israel Medical Center, Harvard Medical School, Boston, MA, United States. Electronic address: sananth@bidmc.harvard.edu.
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D000067128:Extracellular Vesicles; D005260:Female; D018260:Gelsolin / Q000097:blood* / Q000494:pharmacology*; D006801:Humans; D011225:Pre-Eclampsia / Q000097:blood*; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D011994:Recombinant Proteins / Q000494:pharmacology*; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000187:drug effects* / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D018260:Gelsolin; D011994:Recombinant Proteins; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Dynamic stretch; Gelsolin; Preeclampsia; Syncytiotrophoblastic microparticle shedding; sFlt1