Vascular smooth muscle maintains the levels of Bcl-2 in endothelial cells.
Endothelial cells (ECs) play important roles in maintaining vascular homeostasis. Therefore, dysregulation of EC apoptosis may be involved in the mechanism of atherogenesis. Since recent evidence has shown that vascular endothelial growth factor (VEGF), an EC-specific growth factor, is released from vascular smooth muscle cells (VSMCs), we examined whether VSMCs can modulate EC apoptosis using a coculture system. Incubation of ECs with high levels of nitric oxide (NO) released by N-ethyl-2-[1-ethyl-2-hydroxy-2-nitrosohydrazino]-ethanamine, a NO releasing agent, resulted in apoptosis in association with decreased levels of Bcl-2, and increased levels of Bax, an accelerator of aoptosis. Exogenously added VEGF partially inhibited apoptosis and alterations of these bcl-2 family proteins induced by NO. On the other hand, NO-induced apoptosis and down-regulation of Bcl-2 in ECs were almost completely inhibited by coculturing with VSMCs. However, these inhibitory effects by VSMCs were suppressed by a neutralizing antibody against VEGF. In addition, overexpression of Bcl-2 prevented from NO-induced apoptosis in ECs. These findings indicate that VSMCs protect ECs from NO-induced apoptosis through inhibiting down-regulation of Bcl-2. Thus, vascular smooth muscle which releases EC survival factors including VEGF may play important roles in maintaining the levels of Bcl-2 in ECs.
Hata
S
S
Department of Geriatric Medicine, Biomedical Research Center, Osaka University Medical School, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan.
Fukuo
K
K
Morimoto
S
S
Eguchi
Y
Y
Tsujimoto
Y
Y
Ogihara
T
T
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008222:Lymphokines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D020033:Protein Isoforms / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D016228:Endothelial Growth Factors; D008222:Lymphokines; C093285:NOC 18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051028:bcl-2-Associated X Protein