title: Notch activation mediates angiotensin II-induced vascular remodeling by promoting the proliferation and migration of vascular smooth muscle cells.
abstract: Notch signaling is involved in an intercellular communication mechanism that is essential for coordinated cell fate determination and tissue morphogenesis. The biological effects of Notch signaling are context-dependent. We investigated the functional and hierarchical relationship between angiotensin (Ang) II receptor signaling and Notch signaling in vascular smooth muscle cells (VSMCs). A fluorogenic substrate assay revealed directly that the enzymatic activity of γ-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by γ-secretase was consistently induced and peaked at 10 min after Ang II stimulation, and the Ang II-stimulated increase in Notch intracellular domain production was significantly suppressed by treatment with the γ-secretase inhibitor DAPT. Treatment with DAPT also significantly reduced the Ang II-stimulated proliferation and migration of human aortic VSMCs, as revealed by BrdU incorporation and the Boyden chamber assay, respectively. Systemic administration of the γ-secretase inhibitor dibenzazepine reduced Ang II-induced medial thickening and perivascular fibrosis in the aortas of wild-type mice. These findings suggest that the hierarchical Ang II receptor-Notch signaling pathway promotes the proliferation and migration of VSMCs, and thereby contributes to the progression of vascular remodeling.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ozasa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Qin
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tateno
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ito
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kudo-Sakamoto
authors.forename: Masamichi
authors.initials: M
authors.lastname: Yano
authors.forename: Chizuru
authors.initials: C
authors.lastname: Yabumoto
authors.forename: Atsuhiko T
authors.initials: AT
authors.lastname: Naito
authors.forename: Toru
authors.initials: T
authors.lastname: Oka
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagai
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003984:Dibenzazepines / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D051880:Receptors, Notch / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D003984:Dibenzazepines; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D044140:Receptor, Angiotensin, Type 1; D051880:Receptors, Notch; D000804:Angiotensin II; D053829:Amyloid Precursor Protein Secretases; C527817:dibenzazepine