Upregulation of angiotensin-converting enzyme by vascular endothelial growth factor.
The role of vascular endothelial growth factor (VEGF), a potent endothelium-specific angiogenic factor, in the regulation of angiotensin-converting enzyme (ACE) in cultured human umbilical vein endothelial cells (HUVECs) was studied. VEGF (0.07-1.2 x 10(-6) mmol/l) caused a dose-dependent increase in ACE measured in intact endothelial cells and increased the expression of ACE mRNA. The stimulatory effect of VEGF was inhibited by pretreatment of endothelial cells with the tyrosine kinase inhibitor herbimycin (4.35 x 10(-5) mmol/l). The stimulatory effect of VEGF was potentiated by the selective cGMP phosphodiesterase inhibitor zaprinast (0.1 mmol/l). The nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 5.4 mmol/l) suppressed the stimulatory effect of VEGF. The nonselective cyclooxygenase (COX) inhibitor indomethacin (5 microM) and the selective COX-2 inhibitor NS-398 (5 microM) potentiated the stimulatory effect of VEGF, whereas the selective COX-1 inhibitor resveratrol (5 microM) was without effect. ACE induction by VEGF was inhibited by the selective protein kinase C (PKC) inhibitor GF109203X (2.5 x 10(-3) mmol/l) and by downregulating PKC with phorbol 12-myristate 13-acetate. In summary, VEGF induced ACE in cultured HUVECs. Intracellular events such as tyrosine kinase activation, PKC activation, and increase of cGMP were probably involved in ACE induction by VEGF. Nitric oxide may partially contribute to ACE induction by VEGF. The powerful capacity of VEGF to increase ACE in endothelial cells shown here suggests a synergistic relation between VEGF and the renin-angiotensin system in vascular biology and pathophysiology.
Saijonmaa
O
O
Minerva Institute for Medical Research, Helsinki University Central Hospital, SF-00250 Helsinki, Finland. Outi.Saijonmaa@helsinki.fi
Nyman
T
T
Kosonen
R
R
Fyhrquist
F
F
D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008222:Lymphokines / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000201:enzymology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016227:Benzoquinones; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007211:Indoles; D047029:Lactams, Macrocyclic; D008222:Lymphokines; D008301:Maleimides; D009578:Nitrobenzenes; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011809:Quinones; D012333:RNA, Messenger; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D017828:Rifabutin; D009569:Nitric Oxide; C020754:herbimycin; D011464:Epoprostenol; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D007703:Peptidyl-Dipeptidase A; C011145:zaprinast; D006152:Cyclic GMP; C070515:bisindolylmaleimide I; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin