PGE(2) stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways.
Vascular endothelial growth factor (VEGF) plays an essential role in the initiation and regulation of angiogenesis-a crucial component of wound healing and cancer growth. Prostaglandins (PGs) stimulate angiogenesis but the precise mechanisms of their pro-angiogenic actions remain unexplained. We investigated whether prostaglandin E(2) (PGE(2)) can induce VEGF expression in rat gastric microvascular endothelial cells (RGMEC) and the signaling pathway(s) involved. We demonstrated that PGE(2) significantly increased ERK2 and JNK1 activation and VEGF mRNA and protein expression. Incubation of RGMEC with PD 98059 (MEK kinase inhibitor) significantly reduced PGE(2)-induced ERK2 activity, VEGF mRNA and protein expression. Furthermore, PD 98059 treatment almost completely abolished JNK1 activation. Our data suggest that PGE(2)-stimulates VEGF expression in RGMEC via transactivation of JNK1 by ERK2. One potential implication of this finding is that increased PG levels in cancers could facilitate tumor growth by stimulating VEGF synthesis and angiogenesis.
Pai
R
R
Medical Service, Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA.
Szabo
I L
IL
Soreghan
B A
BA
Atay
S
S
Kawanaka
H
H
Tarnawski
A S
AS
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D008222:Lymphokines / Q000378:metabolism*; D008833:Microcirculation; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology; D009389:Neovascularization, Pathologic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016895:Culture Media, Serum-Free; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D012313:RNA; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one