title: Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt.
abstract: To determine whether endothelial Akt could affect vascular lesion formation, mutant mice with a constitutively active Akt transgene, which could be inducibly targeted to the vascular endothelium using the tet-off system (EC-Akt Tg mice), were generated. After withdrawal of doxycycline, EC-Akt Tg mice demonstrated increased endothelial-specific Akt activity and NO production. After blood flow cessation caused by carotid artery ligation, neointimal formation was attenuated in induced EC-Akt Tg mice compared with noninduced EC-Akt Tg mice and control littermates. To determine the role of eNOS in mediating these effects, mice were treated with N-nitro-L-arginine methyl ester (L-NAME). Neointimal formation was attenuated to a lesser extent in induced EC-Akt Tg mice treated with L-NAME, suggesting that some of the vascular protective effects were NO independent. Indeed, endothelial activation of Akt resulted in less EC apoptosis in ligated arteries. Immunostaining demonstrated decreased inflammatory and proliferative changes in induced EC-Akt Tg mice after vascular injury. These findings indicate that endothelial activation of Akt suppresses lesion formation via increased NO production, preservation of functional endothelial layer, and suppression of inflammatory and proliferative changes in the vascular wall. These results suggest that enhancing endothelial Akt activity alone could have therapeutic benefits after vascular injury.
authors.affiliation: Vascular Medicine Research Unit, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Mukai
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Rikitake
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wolfrum
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hiroi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
authors.forename: Hyung-Hwan
authors.initials: HH
authors.lastname: Kim
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002339:Carotid Arteries / Q000166:cytology / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation; D005260:Female; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D019331:NG-Nitroarginine Methyl Ester