Notch activation mediates angiotensin II-induced vascular remodeling by promoting the proliferation and migration of vascular smooth muscle cells
Y Ozasa, H Akazawa, Y Qin, K Tateno, K Ito… - Hypertension …, 2013 - nature.com
Y Ozasa, H Akazawa, Y Qin, K Tateno, K Ito, Y Kudo-Sakamoto, M Yano, C Yabumoto…
Hypertension Research, 2013•nature.comNotch 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 …
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 …
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.
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