Pigment epithelium-derived factor (PEDF): a novel trophoblast-derived factor limiting feto-placental angiogenesis in late pregnancy.
The rapidly expanding feto-placental vasculature needs tight control by paracrine and endocrine mechanisms. Here, we focused on paracrine influence by trophoblast, the placental epithelium. We aimed to identify differences in regulation of feto-placental angiogenesis in early versus late pregnancy. To this end, the effect of conditioned media (CM) from early and late pregnancy human trophoblast was tested on network formation, migration and proliferation of human feto-placental endothelial cells. Only CM of late pregnancy trophoblast reduced network formation and migration. Screening of trophoblast transcriptome for anti-angiogenic candidates identified pigment epithelium-derived factor (PEDF) with higher expression and protein secretion in late pregnancy trophoblast. Addition of a PEDF-neutralizing antibody restored the anti-angiogenic effect of CM from late pregnancy trophoblast. Notably, human recombinant PEDF reduced network formation only in combination with VEGF. Also in the CAM assay, the combination of PEDF with VEGF reduced branching of vessels below control levels. Analysis of phosphorylation of ERK1/2 and FAK, two key players in VEGF-induced proliferation and migration, revealed that PEDF altered VEGF signaling, while PEDF alone did not affect phosphorylation of ERK1/2 and FAK. These data suggest that the trophoblast-derived anti-angiogenic molecule PEDF is involved in restricting growth and expansion of the feto-placental endothelium predominantly in late pregnancy and targets to modulate the intracellular effect of VEGF.
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.|Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
Jelena
J
Loegl
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
Erika
E
Nussbaumer
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria. ursula.hiden@medunigraz.at.
Ursula
U
Hiden
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
Alejandro
A
Majali-Martinez
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
Nassim
N
Ghaffari-Tabrizi-Wizy
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.|Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
Silvija
S
Cvitic
Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
Ingrid
I
Lang
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
Gernot
G
Desoye
Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
Berthold
B
Huppertz
D020533:Angiogenesis Inhibitors / Q000502:physiology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D002478:Cells, Cultured; D002642:Chick Embryo; D017077:Culture Media, Conditioned; D005136:Eye Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D005260:Female; D005333:Fetus / Q000098:blood supply* / Q000502:physiology*; D006801:Humans; D018919:Neovascularization, Physiologic; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D019899:Paracrine Communication; D010920:Placenta / Q000098:blood supply* / Q000502:physiology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third; D015843:Serpins / Q000276:immunology / Q000502:physiology*; D014327:Trophoblasts / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology; D000099174:Pigment Epithelium-Derived Factor
D020533:Angiogenesis Inhibitors; D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099174:Pigment Epithelium-Derived Factor; C467484:VEGFA protein, human; C000588866:KDR protein, human
Angiogenesis; Endothelium; PEDF; Placenta; Trophoblast; VEGF