Upregulation of placental growth factor by vascular endothelial growth factor via a post-transcriptional mechanism.
Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are key angiogenic stimulators during normal development and wound healing, as well as in a variety of pathological conditions. Recent studies have demonstrated a synergistic effect of VEGF and PlGF in pathological angiogenesis and suggest a role for PlGF in amplifying VEGF action in endothelial cells. We show here in the mouse model of oxygen-induced retinopathy that VEGF is significantly increased (P<0.01) in the retina at both the mRNA and protein levels. In this mouse model, PlGF was significantly upregulated in the retina at the protein level (P<0.01) without a corresponding change in mRNA levels. In cultured human retinal and umbilical vein endothelial cells, VEGF induced the production of PlGF protein by over 10-fold (P<0.01) in a dose-dependent manner through a post-transcriptional mechanism. The increased PlGF expression upon VEGF treatment was significantly reduced by inhibition of the protein kinase C (PKC) and MEK signaling pathways, as well as by treatment with the calcium ionophore A23187. Taken together, our findings demonstrate that VEGF can amplify its effects on endothelial cells by inducing the production of PlGF via a post-transcriptional mechanism in a PKC-dependent manner, and provide a potential link between PKC inhibition and amelioration of vascular complications in the development of angiogenic diseases.
Yao
Yong-Gang
YG
Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Jefferson 3-109, Baltimore, MD 21287, USA.
Yang
Hoseong S
HS
Cao
Zhiming
Z
Danielsson
Jennifer
J
Duh
Elia J
EJ
D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology*
C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D010703:Phorbol Esters; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C032974:12-O-retinoylphorbol-13-acetate; D011493:Protein Kinase C; D010100:Oxygen