Vascular endothelial growth factor, epidermal growth factor and fibroblast growth factor-4 and -10 stimulate trophoblast plasminogen activator system and metalloproteinase-9.
Trophoblast invasion, accompanied by degradation of extracellular matrix, is crucial to normal pregnancy development, whereas shallow placental invasion and implantation likely plays a role in the subsequent development of pre-eclampsia. The growth factors vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and fibroblast growth factor (FGF) are placental growth factors that activate degradation of extracellular matrix. We determined the effect of VEGF, EGF, FGF-2, FGF-4 and FGF-10 on the plasminogen activator system of first trimester cytotrophoblasts cultured in vitro. We studied the activity of urokinase plasminogen activator (uPA), its inhibitor plasminogen activator inhibitor-1 (PAI-1), and 92 kDa gelatinase-B (matrix metalloproteinase-9, MMP-9), using protein gel and reversed gel zymography. The expression pattern of FGF-4 and FGF-10 in human placental sections was determined by immunohistochemistry. FGF-4 was expressed in first trimester villi stroma, primarily in endothelial cells. FGF-10 expression was localized to first trimester extravillous trophoblasts. VEGF, EGF, FGF-4 and FGF-10, but not FGF-2, stimulate the activity of trophoblast uPA, PAI-1 and MMP-9. These results support the hypothesis that specific growth factors modulate the invasive potential of trophoblasts, and therefore may play an important role in early placental development. Our findings may contribute to the understanding of the pathophysiology of diseases associated with shallow placentation, such as pre-eclampsia.
Department of Obstetrics and Gynecology, Hadassah University Hospital, Mt Scopus, PO Box 24035, Jerusalem 91240, Israel. anteby@cc.huji.ac.il
E Y
EY
Anteby
C
C
Greenfield
S
S
Natanson-Yaron
D
D
Goldman-Wohl
Y
Y
Hamani
V
V
Khudyak
I
I
Ariel
S
S
Yagel
D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D051526:Fibroblast Growth Factor 10; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C496463:FGF10 protein, human; C496445:FGF4 protein, human; D051526:Fibroblast Growth Factor 10; D051519:Fibroblast Growth Factor 4; D017395:Plasminogen Activator Inhibitor 1; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9