Effects of VEGF on Ca(2+)-transient in cultured lymphatic endothelial cells and mechanical activity of isolated lymph vessels.
We investigated the effects of vascular endothelial growth factor (VEGF(165)) on [Ca(2+)](i)-transient in cultured lymphatic endothelial cells (LEC) and mechanical activity of isolated dog thoracic ducts. VEGF (0.1-10 ng/ml) caused a dose-dependent increase of the [Ca(2+)](i) in LEC. Pretreatment with 10(-5) M genistein or 5x10(-6) M herbimycin A produced a significant reduction of the VEGF-induced [Ca(2+)](i)-transient. In the presence of 10(-6) M thapsigargin, VEGF caused no significant effect on the [Ca(2+)](i)-transient. Pretreatment with Ca(2+)-free solution containing 0.1 mM EGTA produced no significant effect on the peak increase of [Ca(2+)](i) induced by 0.1 or 10 ng/ml VEGF, but significantly depressed the sustained part of [Ca(2+)](i) observed at the higher concentration of VEGF. The VEGF (0.1-10 ng/ml) caused a significant dilation of the isolated lymph vessels with intact endothelium, which were precontracted with U46,619. The 10 ng/ml VEGF-induced dilation was significantly reduced by 3 x 10(-5) M N(omega)-nitro-L-arginine methyl ester (L-NAME). The action of L-NAME was inhibited by the simultaneous application of 10(-3) M L-arginine. Mechanical rubbing of the endothelium also caused significant inhibition of the VEGF-induced dilation. The findings suggest that VEGF(165) may activate the receptor-related tyrosine kinase and cause the release of Ca(2+) from the inositol 1,4, 5-triphosphate-sensitive intracellular Ca(2+) stores in LEC. VEGF(165) also produces endothelium-dependent nitric oxide-mediated dilation of the precontracted isolated lymph vessels.
Arai
F
F
The 1st Department of Physiology, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan.
Mizuno
R
R
Ohhashi
T
T
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D016227:Benzoquinones; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004285:Dogs; D004533:Egtazic Acid / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004729:Endothelium, Lymphatic / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019833:Genistein / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D047029:Lactams, Macrocyclic; D008196:Lymph / Q000378:metabolism; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D013314:Stress, Mechanical; D019284:Thapsigargin / Q000494:pharmacology; D013897:Thoracic Duct / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D002614:Chelating Agents; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D047029:Lactams, Macrocyclic; D008222:Lymphokines; D011809:Quinones; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D017828:Rifabutin; D009569:Nitric Oxide; D004533:Egtazic Acid; D019284:Thapsigargin; C020754:herbimycin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001120:Arginine; D019833:Genistein; D011188:Potassium; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester