Involvement of gamma-secretase in postnatal angiogenesis.
gamma-Secretase cleaves the transmembrane domains of several integral membrane proteins involved in vasculogenesis. Here, we investigated the role of gamma-secretase in the regulation of postnatal angiogenesis using gamma-secretase inhibitors (GSI). In endothelial cell (EC), gamma-secretase activity was up-regulated under hypoxia or the treatment of vascular endothelial growth factor (VEGF). The treatment of GSI significantly attenuated growth factor-induced EC proliferation and migration as well as c-fos promoter activity in a dose-dependent manner. In vascular smooth muscle cell (VSMC), treatment of GSI significantly attenuated growth factor-induced VEGF and fibroblast growth factor-2 (FGF-2) expression. Indeed, GSI attenuated VEGF-induced tube formation and inhibited FGF-2-induced angiogenesis on matrigel in mice as quantified by FITC-lectin staining of EC. Overall, we demonstrated that gamma-secretase may be key molecule in postnatal angiogenesis which may be downstream molecule of growth factor-induced growth and migration in EC, and regulate the expression of angiogenic growth factors in VSMC.
Hayashi
Hiroki
H
Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nakagami
Hironori
H
Takami
Yoichi
Y
Sato
Naoyuki
N
Saito
Yukihiro
Y
Nishikawa
Tomoyuki
T
Mori
Masaki
M
Koriyama
Hiroshi
H
Tamai
Katsuto
K
Morishita
Ryuichi
R
Kaneda
Yasufumi
Y
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D015153:Blotting, Western; D002219:Carbamates / Q000494:pharmacology; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016760:Proto-Oncogene Proteins c-fos; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D053829:Amyloid Precursor Protein Secretases