期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 284, 期 1, 页码 H92-H100出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00330.2002
关键词
microvascular permeability; mitogen-activated protein kinases; endothelial cells; vascular endothelial growth factor; protein kinase C
资金
- NHLBI NIH HHS [K08-HL-03354, 1R01-HL-70634, K07-HL-03437] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [K08HL003354, K07HL003437, R01HL070634] Funding Source: NIH RePORTER
We tested the hypothesis that VEGF regulates endothelial hyperpermeability to macromolecules by activating the ERK-1/2 MAPK pathway. We also tested whether PKC and nitric oxide (NO) mediate VEGF-induced increases in permeability via the ERK-1/2 pathway. FITC-Dextran 70 flux across human umbilical vein endothelial cell monolayers served as an index of permeability, whereas Western blots assessed the phosphorylation of ERK-1/2. VEGF-induced hyperpermeability was inhibited by antisense DNA oligonucleotides directed against ERK-1/2 and by blockade of MEK and Raf-1 activities (20 muM PD-98059 and 5 muM GW-5074). These blocking agents also reduced ERK-1/2 phosphorylation. The PKC inhibitor bisindolylmaleimide I (10 muM) blocked both VEGF-induced ERK-1/2 activation and hyperpermeability. The NO synthase (NOS) inhibitor N-G-nitro-L-arginine methyl ester (200 muM) and the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidiazoline- 1-oxyl-3-oxide (100 muM) abolished VEGF-induced hyperpermeability but did not block ERK-1/2 phosphorylation. These observations demonstrate VEGF-induced hyperpermeability involves activation of PKC and NOS as well as Raf-1, MEK, and ERK-1/2. Furthermore, our data suggest that ERK-1/2 and NOS are elements of different signaling pathways in VEGF-induced hyperpermeability.
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