Vascular endothelial growth factor induces endothelin-1 production via matrix metalloproteinase-2 rather than endothelin-converting enzyme-1.
OBJECTIVE
To investigate the mechanism of vascular endothelial growth factor (VEGF)-induced endothelin-1 production in human umbilical vein endothelial cells (HUVECs).


METHODS
Endothelin-1 levels were measured in conditioned medium of women with preeclampsia HUVECs were treated with different concentrations of VEGF(165) and at various time intervals. Next, we measured endothelin-1 levels after HUVECs were also incubated with VEGF and endothelin-converting enzyme-1 (ECE-1) inhibitor or tissue inhibitors of matrix metalloproteinase-2 (TIMP-2). Additionally, the circulating levels of total and free VEGF, matrix metalloproteinase-2 (MMP-2), and endothelin-1 were measured in 20 preeclamptic patients and 20 healthy pregnant controls.


RESULTS
HUVECs treated with VEGF increased their endothelin-1 production in a concentration and time-dependent manner. The production of endothelin-1 was inhibited by TIMP-2, but not by the ECE-1 inhibitor. Total VEGF, MMP-2, and endothelin-1 concentrations were higher in preeclampsia and showed significant positive correlations between them.


CONCLUSIONS
These findings suggest that VEGF-induced endothelin-1 production might be mediated by MMP-2 rather than by ECE-1 upregulation.
Lee
Kyung-Ju
KJ
Department of Obstetrics and Gynecology, College of Medicine, Pochon CHA University, Pochon, Kyunggi, Korea.
Kim
Meyoung-Kon
MK
Park
Yoon-Hee
YH
Seol
Hyun-Joo
HJ
Lim
Ji-Eun
JE
Lee
Jeong No
JN
Oh
Min-Jeong
MJ
D000328:Adult; D000704:Analysis of Variance; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000187:drug effects*; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007723:Korea; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000097:blood; D011225:Pre-Eclampsia / Q000188:drug therapy / Q000378:metabolism; D011247:Pregnancy; D013997:Time Factors; D016896:Treatment Outcome; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism*
D015415:Biomarkers; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes