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Smooth muscle SIRT1 reprograms endothelial cells to suppress angiogenesis after ischemia
Vascular smooth muscle cells (VSMCs) undergo the phenotypic changes from contractile to synthetic state during vascular remodeling after ischemia. SIRT1 protects against stress-induced vascular remodeling via maintaining VSMC differentiated phenotype. However, the effect of smooth muscle SIRT1 on th...
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Published in: | Theranostics 2020, Vol.10 (3), p.1197-1212 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that cite this one |
Online Access: | Get full text |
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Summary: | Vascular smooth muscle cells (VSMCs) undergo the phenotypic changes from contractile to synthetic state during vascular remodeling after ischemia. SIRT1 protects against stress-induced vascular remodeling via maintaining VSMC differentiated phenotype. However, the effect of smooth muscle SIRT1 on the functions of endothelial cells (ECs) has not been well clarified. Here, we explored the role of smooth muscle SIRT1 in endothelial angiogenesis after ischemia and the underlying mechanisms.
We performed a femoral artery ligation model using VSMC specific human SIRT1 transgenic (
-Tg) and knockout (KO) mice. Angiogenesis was assessed in
by quantification of the total number of capillaries, wound healing and matrigel plug assays, and
ECs by tube formation, proliferation and migration assays. The interaction of HIF1α with circRNA was examined by using RNA immunoprecipitation, RNA pull-down and
hybridization assays.
The blood flow recovery was significantly attenuated in
-Tg mice, and markedly improved in
-Tg mice treated with SIRT1 inhibitor EX527 and in
-KO mice. The density of capillaries significantly decreased in the ischemic gastrocnemius of
Tg mice compared with
-KO and WT mice, with reduced expression of VEGFA, which resulted in decreased number of arterioles. We identified that the phenotypic switching of
-Tg VSMCs was attenuated in response to hypoxia, with high levels of contractile proteins and reduced expression of the synthetic markers and NG2, compared with
-KO and WT VSMCs. Mechanistically,
-Tg VSMCs inhibited endothelial angiogenic activity induced by hypoxia via the exosome cZFP609. The cZFP609 was delivered into ECs, and detained HIF1α in the cytoplasm via its interaction with HIF1α, thereby inhibiting VEGFA expression and endothelial angiogenic functions. Meantime, the high cZFP609 expression was observed in the plasma of the patients with atherosclerotic or diabetic lower extremity peripheral artery disease, associated with reduced ankle-brachial index. Knockdown of cZFP609 improved blood flow recovery after hindlimb ischemia in
Tg mice.
: Our findings demonstrate that SIRT1 may impair the plasticity of VSMCs. cZFP609 mediates VSMCs to reprogram endothelial functions, and serves as a valuable indicator to assess the prognosis and clinical outcomes of ischemic diseases. |
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ISSN: | 1838-7640 1838-7640 |
DOI: | 10.7150/thno.39320 |