Notch activation mediates angiotensin II-induced vascular remodeling by promoting the proliferation and migration of vascular smooth muscle cells
Notch activation mediates angiotensin II-induced vascular remodeling by promoting the proliferation and migration of vascular smooth muscle cells
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DOI：
10.1038/hr.2013.52
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发表时间：
2013-10-01
影响因子：
5.4
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Ozasa, Yukako;Akazawa, Hiroshi;Komuro, Issei
Notch信号转导参与细胞间通讯机制，该机制对于协调细胞命运决定和组织形态发生至关重要。Notch信号传导的生物学效应是情境依赖性的。我们研究了血管紧张素（Ang）II受体信号和Notch信号在血管平滑肌细胞（VSMCs）中的功能和层次关系。荧光底物测定直接显示，在表达Ang II 1型受体的HEK 293细胞中，Ang II刺激10分钟后，γ-分泌酶的酶活性增强。Notch裂解的γ-分泌酶诱导一致，并在10分钟后达到峰值，血管紧张素II刺激后，Notch细胞内结构域的生产增加显着抑制治疗与γ-分泌酶抑制剂DAPT。用DAPT处理也显著降低了Ang II刺激的人主动脉VSMCs的增殖和迁移，分别通过BrdU掺入和Boyden室测定显示。全身给予γ-分泌酶抑制剂二苯并氮杂卓可减少野生型小鼠睾丸中血管紧张素II诱导的中膜增厚和血管周围纤维化。这些结果表明，分级的Ang II受体-Notch信号通路促进VSMCs的增殖和迁移，从而有助于血管重塑的进展。
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 gamma-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by gamma-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 gamma-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 gamma-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.