title: Intra-amniotic infection upregulates decidual cell vascular endothelial growth factor (VEGF) and neuropilin-1 and -2 expression: implications for infection-related preterm birth.
abstract: Intra-amniotic infection/inflammation (IAI) is a major cause of preterm birth, but the mechanisms responsible are not well understood. This study investigates the effects of IAI on vascular endothelial growth factor (VEGF) as well as VEGF receptor (Flt1, KDR2) and coreceptor (neuropilin-1 and -2) messenger RNA (mRNA) and protein expression at the maternal-fetal interface, both in vitro and in vivo. Decidual stromal cells (DSCs) were isolated from term placentae, purified, and treated with 10(-8) mol/L estradiol (E(2)), 10( -7) mol/L medroxyprogesterone acetate (MPA), both, or vehicle for 7 days. Vascular endothelial growth factor expression in cultured DSCs increased in response to stimulation with interleukin 1 beta (IL-1 beta; 0.01-10 ng/mL)--but not tumor necrosis factor alpha (TNF-alpha; 1 ng/mL)--in a concentration-dependent fashion irrespective of the hormonal milieu. This effect appears to be mediated at the level of gene transcription because stimulation with IL-1 beta (but not TNF-alpha) increased expression of VEGF mRNA as measured by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR); a similar increase was seen in neuropilin-1/-2 (but not Flt1 and KDR2) mRNA. Immunohistochemical studies confirmed these observations in vivo. Immunostaining for VEGF and neuropilin-1/-2 (but not Flt1 or KDR2) was increased in serial tissue sections of decidua from women with clinical and histological evidence of IAI versus noninfected controls, and in cultured term DSCs exposed to IL-1 beta. The novel observations that IL-1 beta stimulates VEGF and neuropilin-1/-2 mRNA and protein expression in term DSCs in vitro along with confirmatory in vivo data using immunohistochemistry provide a mechanism by which IAI can alter vascular permeability, thereby facilitating leukocyte trafficking and increasing the risk of abruption, both of which are associated with preterm birth.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Victoria V
authors.initials: VV
authors.lastname: Snegovskikh
authors.forename: Frederick
authors.initials: F
authors.lastname: Schatz
authors.forename: Felice
authors.initials: F
authors.lastname: Arcuri
authors.forename: Paolo
authors.initials: P
authors.lastname: Toti
authors.forename: Umit A
authors.initials: UA
authors.lastname: Kayisli
authors.forename: William
authors.initials: W
authors.lastname: Murk
authors.lastname: Guoyang Luo
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lockwood
authors.forename: Errol R
authors.initials: ER
authors.lastname: Norwitz
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D002821:Chorioamnionitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003656:Decidua / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D039943:Neuropilin-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1