title: GDM alters paracrine regulation of feto-placental angiogenesis via the trophoblast.
abstract: Feto-placental angiogenesis and vascular development are tightly regulated by pro- and anti-angiogenic factors. Villous trophoblast may be a major source of these factors. It forms the classical placental barrier between mother and fetus, and is thus exposed to maternal influences as well. Metabolic and hormonal derangements in gestational diabetes mellitus (GDM) affect feto-placental angiogenesis and vascular growth. Here we hypothesized that GDM alters the trophoblast secretome, which will modulate the paracrine regulation of feto-placental angiogenesis. Primary term trophoblasts were isolated from normal (n=6) and GDM (n=6) pregnancies. Trophoblast conditioned medium (CM) was used to investigate paracrine effects of normal and GDM-exposed trophoblasts on feto-placental endothelial cells (fpECs; n=7), using functional assays for 2D network formation, wound healing, chemotaxis, and proliferation. Gene expression of 23 pro- and anti-angiogenic factors was analyzed. Four trophoblast-derived paracrine regulators of angiogenesis were specifically measured in CM. CM from GDM trophoblasts increased 2D network formation of fpEC by 2.4-fold (P<0.001), whereas wound healing was attenuated by 1.8-fold (P=0.02) and chemo-attraction to the CM was reduced by 33±9% (P=0.02). The effect of CM on proliferation was unchanged between normal and GDM trophoblasts. Expression analysis of pro- and anti-angiogenic molecules in normal and GDM trophoblasts revealed significant differences in ANGPT2, HGF, KISS1 and PLGF expression. Analysis of secreted proteins demonstrated reduced pigment epithelium derived factor and tumor necrosis factor-α secretion by GDM trophoblasts. GDM alters the balance of trophoblast derived, angiogenesis modulating paracrine factors. This may contribute to GDM-associated changes in placental angiogenesis and vascular structure.
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
authors.forename: Jelena
authors.initials: J
authors.lastname: Loegl
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
authors.forename: Erika
authors.initials: E
authors.lastname: Nussbaumer
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.|Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
authors.forename: Silvija
authors.initials: S
authors.lastname: Cvitic
authors.affiliation: Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
authors.forename: Berthold
authors.initials: B
authors.lastname: Huppertz
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Desoye
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Hiden
mesh_terms: D000328:Adult; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016640:Diabetes, Gestational / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005333:Fetus / Q000098:blood supply; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D059648:Kisspeptins / Q000235:genetics; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D010920:Placenta / Q000098:blood supply; D000072483:Placenta Growth Factor / Q000235:genetics; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014327:Trophoblasts / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D017077:Culture Media, Conditioned; C106628:KISS1 protein, human; D059648:Kisspeptins; C000608036:PGF protein, human; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D000072483:Placenta Growth Factor; D017228:Hepatocyte Growth Factor