Regulation of endothelial glutathione by ICAM-1 governs VEGF-A-mediated eNOS activity and angiogenesis.
Previous studies suggest that inflammatory cell adhesion molecules may modulate endothelial cell migration and angiogenesis through unknown mechanisms. Using a combination of in vitro and in vivo approaches, herein we reveal a novel redox-sensitive mechanism by which ICAM-1 modulates endothelial GSH that controls VEGF-A-induced eNOS activity, endothelial chemotaxis, and angiogenesis. In vivo disk angiogenesis assays showed attenuated VEGF-A-mediated angiogenesis in ICAM-1(-/-) mice. Moreover, VEGF-A-dependent chemotaxis, eNOS phosphorylation, and nitric oxide production were impaired in ICAM-1(-/-) mouse aortic endothelial cells (MAEC) compared to WT MAEC. Decreasing intracellular GSH in ICAM-1(-/-) MAEC to levels observed in WT MAEC with 150 microM buthionine sulfoximine restored VEGF-A responses. Conversely, GSH supplementation of WT MAEC with 5 mM glutathione ethyl ester mimicked defects observed in ICAM-1(-/-) cells. Deficient angiogenic responses in ICAM-1(-/-) cells were associated with increased expression of the lipid phosphatase PTEN, consistent with antagonism of signaling pathways leading to eNOS activation. PTEN expression was also sensitive to GSH status, decreasing or increasing in proportion to intracellular GSH concentrations. These data suggest a novel role for ICAM-1 in modulating VEGF-A-induced angiogenesis and eNOS activity through regulation of PTEN expression via modulation of intracellular GSH status.
Langston
Will
W
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, 1501 Kings Highway, Shreveport, LA 71130, USA.
Chidlow
John H
JH
Booth
Blake A
BA
Barlow
Shayne C
SC
Lefer
David J
DJ
Patel
Rakesh P
RP
Kevil
Christopher G
CG
D000818:Animals; D001011:Aorta / Q000378:metabolism; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D018799:Intercellular Adhesion Molecule-1; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005978:Glutathione